Oxazolone Derivatives

ABSTRACT

Novel raw material compounds are provided that are useful for producing novel cycloalkane carboxamide derivatives having cathepsin K inhibitory action. 
     An oxazolone derivative represented by formula (I): 
     
       
         
         
             
             
         
       
     
     [wherein, R 1  represents a substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted phenyl group, substituted or unsubstituted naphthyl group or substituted or unsubstituted heterocyclic group, and ring A represents a saturated cyclic alkylidene group having 6 to 7 carbon atoms].

TECHNICAL FIELD

The present invention relates to novel oxazolone derivatives. Moreparticularly, the present invention relates to novel oxazolonederivatives useful as raw material intermediates for producingcycloalkane carboxamide derivatives having the action of selectivelyinhibiting cathepsin K, which is the main cysteine protease involved inbone resorption.

BACKGROUND ART

Accompanying the rapid progression to an elderly society in recentyears, the number of patients with geriatric diseases, and particularlythose with bone diseases, is continuing to increase. In particular,osteoporosis, which is prevalent among women and especiallypostmenopausal women, is becoming a serious problem. Since acceleratedbone resorption brought about by hormonal imbalance and aging phenomenain postmenopausal women is intimately related to the onset andprogression of bone disease, bone resorption inhibitors have been usedduring the course of ordinary drug therapy for osteoporosis. However,drugs currently in use that demonstrate bone resorption inhibitoryaction, such as calcitonin preparations, estrogen preparations, vitaminK preparations and bisphosphonate preparations, have problems in termsof their therapeutic effects, rapid-acting, adverse side effects andpatient compliance, thus desiring the development of a bone resorptioninhibitor capable of being used as a more effective drug for thetreatment or prevention of osteoporosis.

In the living body, bone calcium concentrations and blood calciumconcentrations are in a state of equilibrium, and calcium is constantlymigrating between the bone and blood. This migration of calcium betweenthe bone and blood is governed by dynamic shifts between bone formationand bone resorption. In the process of bone resorption, bone resorptionis known to be accelerated as a result of activated osteoclasts elutingbone inorganic substances such as calcium simultaneous to cysteineproteases secreted from osteoclasts decomposing bone organic substancessuch as collagen. Cysteine proteases such as cathepsin B, cathepsin H,cathepsin L and cathepsin S are present in osteoclast lysosomes, andosteoclast-localized human cathepsin K was isolated in 1995, which wasdemonstrated to be expressed in osteoclasts in larger amounts than othercathepsins (Biochem. Biophys. Res. Commun., 206, 89 (1995); J. Biol.Chem., 271, 12511 (1996)). Moreover, the cathepsin K gene wasdemonstrated to mutate in patients with dwarfism presenting with boneresorption abnormalities (Science, 273, 1236 (1997)).

In this manner, attention has been focused on cathepsin K as the maincysteine protease involved in bone resorption, and considerableexpectations are being placed on cathepsin K inhibitors as inhibitors ofbone resorption. Previously reported examples of compounds havingcathepsin K inhibitory action include aldehyde derivatives, epoxysuccinic acid derivatives (J. Biol. Chem., 271, p. 2126 (1996); Biol.Pharm. Bull., 19, p. 1026 (1996)) and vinylsulfonic acid derivatives(Nature Structural Biology, 4, p. 105 (1997); J. Med. Chem., 38, p. 3139(1995)), and these derivatives have low selectivity and are known tostrongly inhibit other cysteine proteases in addition to cathepsin K (J.Enzyme Inhibition, 3, p. 13 (1989); Biochem. Biophys. Res. Commun., 153,p. 1201 (1988); J. Biochem., 87, p. 39 (1980); J. Biochem., 88, p. 1805(1980)).

Moreover, accompanying the growing interest in cathepsin K as describedabove, research has also been actively conducted in the area of X-raycrystal analyses of cathepsin K and inhibitors (Nature StructuralBiology, 4, p. 105 (1997); Nature Structural Biology, 4, p. 109 (1997)),and compounds are known that have a selective inhibitory action oncathepsin K (Proc. Natl. Acad. Sci. USA, 94, 142, p. 49 (1997);WO9801133; J. Am. Chem. Soc., 120, 9, p. 114 (1998); J. Med. Chem., 41,p. 3563 (1988); Japanese Unexamined Patent Publication No. 2000-204071;Bioorg. Med. Chem., 14, p. 4333 (2004); Bioorg. Med. Chem., 14, p. 4897(2004)). In addition, WO971677 identifies the catalyst active site ofcathepsin K and discloses a method for inhibiting cathepsin K using acompound that interacts with this active site.

[Non-Patent Document 1] Proc. Natl. Acad. Sci. USA, 94, 142, 49 (1997)

[Non-Patent Document 2] J. Am. Chem. Soc., 120, 9, 114 (1998)

[Non-Patent Document 3] J. Med. Chem., 41, 3563 (1998)

[Non-Patent Document 4] Bioorg. Med. Chem., 14, 4333 (2004)

[Non-Patent Document 5] Bioorg. Med. Chem., 14, 4897 (2004)

[Patent Document 1] WO9801133

[Patent Document 2] WO971677

[Patent Document 3] Japanese Unexamined Patent Publication No.2000-204071

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

As has been described above, compounds that inhibit cathepsin K haveattracted attention as bone resorption inhibitors, and although numerousderivatives have been reported, none has yet been able to be usedpractically as a therapeutic drug for metabolic bone diseases. As aresult of conductive extensive studies on novel compounds having potentand selective cathepsin K inhibitory action, the inventors of thepresent invention found that novel cycloalkane carboxamide derivativesrepresented by a specific structural formula selectively inhibitcathepsin K as compared with conventional aldehyde derivatives known tobe compounds having cathepsin K inhibitory action.

An object of the present invention is to provide novel raw materialcompounds useful for producing these novel cycloalkane carboxamidederivatives.

Means for Solving the Problems

The present invention relates to novel raw material compounds forproducing cycloalkane carboxamide derivatives represented by thefollowing formula (XIII) having selective inhibitory activity againstcathepsin K, and the gist thereof lies in the oxazolone derivativesdescribed in 1 to 5 below.

1. An oxazolone derivative represented by formula (I):

[wherein, R¹ represents an unsubstituted alkyl group having 3 to 12carbon atoms, an alkyl group having 1 to 12 carbon atoms substitutedwith at least one substituent selected from the following group (a), analkenyl group having 2 to 12 carbon atoms optionally substituted with atleast one substituent selected from the following group (a), an alkynylgroup having 2 to 12 carbon atoms optionally substituted with at leastone substituent selected from the following group (a), a phenyl groupsubstituted with at least one substituent selected from the followinggroup (b), a naphthyl group optionally substituted with at least onesubstituent selected from the following group (a), or a heterocyclicgroup optionally substituted with at least one substituent selected fromthe following group (a); and, ring A represents a saturated cyclicalkylidene group having 6 to 7 carbon atoms;

provided that, the heterocyclic group does not form a spiro ring, analkyl group having 1 to 12 carbon atoms substituted with at least onesubstituent selected from the group (a) does not include a cyclohexylgroup substituted with an amino group and a phenylmethoxycarbonylaminogroup, an isobutyl group substituted with a phenylmethylamino group, a3-pentyl group substituted with a heterocyclic group or a1-carbonylaminocyclohexane carboxyl group, or an n-butyl groupsubstituted with 3-oxa-1-azaspiro[4.5]dec-1-ene-4-one, and, anunsubstituted alkenyl group does not include a vinyl group and apropenyl group, and a substituted phenyl group does not simultaneouslyhave a methyl group and a methoxy group on the same benzene ring];

group (a):

hydroxyl group, alkyl group, alkenyl group, alkynyl group, fluorineatom, chlorine atom, iodine atom, bromine atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, and Rx(Ry)N group (wherein, Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group); and

group (b):

hydroxyl group, alkyl group, alkenyl group, alkynyl group, fluorineatom, chlorine atom, iodine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, and Rx(Ry)N group (wherein, Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group).

2. An oxazolone derivative represented by formula (I′):

[wherein, R^(1′) represents an unsubstituted alkyl group having 3 to 12carbon atoms, an alkyl group having 1 to 12 carbon atoms substitutedwith at least one substituent selected from the following group (a₁), anunsubstituted alkenyl group having 4 to 12 carbon atoms, an alkenylgroup having 2 to 12 carbon atoms substituted with at least onesubstituent selected from the following group (a), an alkynyl grouphaving 2 to 12 carbon atoms optionally substituted with at least onesubstituent selected from the following group (a), a phenyl groupsubstituted with at least one substituent selected from the followinggroup (b₁), a naphthyl group optionally substituted with at least onesubstituent selected from the following group (a), or a heterocyclicgroup optionally substituted with at least one substituent selected fromthe following group (a); and, ring A represents a saturated cyclicalkylidene group having 6 to 7 carbon atoms, provided that theheterocyclic group does not form a spiro ring];

group (a₁):

hydroxyl group, alkyl group, alkenyl group, alkynyl group, fluorineatom, chlorine atom, iodine atom, bromine atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, oxo group, sulfamoyl group, sulfogroup, cyano group, nitro group, acyloxy group, azido group, sulfonamidogroup, and mercapto group;

group (a):

hydroxyl group, alkyl group, alkenyl group, alkynyl group, fluorineatom, chlorine atom, iodine atom, bromine atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, and Rx(Ry)N group (wherein, Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group); and

group (b₁):

hydroxyl group, alkyl group having 2 to 12 carbon atoms, alkenyl group,alkynyl group, fluorine atom, chlorine atom, iodine atom, aromatichydrocarbon group, heterocyclic group, alkoxy group, guanidino group,alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group,acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthiogroup, amido group, ureido group, carboxyl group, carbamoyl group, oxogroup, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxygroup, azido group, sulfonamido group, mercapto group,alkoxycarbonylamino group, and Rx(Ry)N group (wherein, Rx and Ryrespectively and independently represent a hydrogen atom, alkyl group,alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclicgroup).

3. An oxazolone derivative represented by formula (I″):

[wherein, R^(1″) represents an unsubstituted alkenyl group having 4 to12 carbon atoms, an alkenyl group having 2 to 12 carbon atomssubstituted with at least one substituent selected from the followinggroup (a), an alkynyl group having 2 to 12 carbon atoms optionallysubstituted with at least one substituent selected from the followinggroup (a), a phenyl group substituted with at least one substituentselected from the following group (b₁), a naphthyl group optionallysubstituted with a substituent selected from the following group (a), aheterocyclic group optionally substituted with at least one substituentselected from the following group (a), or a group represented byRa(Rb)CH—, and ring A represents a saturated cyclic alkylidene grouphaving 6 to 7 carbon atoms;

wherein, in the case both Ra and Rb are not hydrogen atoms, Ra and Rbrepresent a hydroxyl group, fluorine atom, chlorine atom, iodine atom,bromine atom, aromatic hydrocarbon group, heterocyclic group, alkoxygroup, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxygroup, arylthio group, acyl group, sulfonyl group, heterocyclyloxygroup, heterocyclylthio group, amido group, ureido group, carboxylgroup, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyanogroup, nitro group, acyloxy group, azido group, sulfonamido group,mercapto group, alkoxycarbonylamino group, Rx(Ry)N group (wherein, Rxand Ry respectively and independently represent a hydrogen atom, alkylgroup, alkenyl group, alkynyl group, aromatic hydrocarbon group orheterocyclic group), an alkyl group having 1 to 12 carbon atomssubstituted with at least one substituent selected from the followinggroup (a), unsubstituted alkyl group having 1 to 12 carbon atoms, phenylgroup optionally substituted with at least one substituent selected fromthe following group (a), naphthyl group optionally substituted with atleast one substituent selected from the following group (a),heterocyclic group optionally substituted with at least one substituentselected from the following group (a), alkyl group having 1 to 12 carbonatoms optionally substituted with at least one substituent selected fromthe following group (a), aromatic hydrocarbon group optionallysubstituted with at least one substituent selected from the followinggroup (a), or heterocyclic group optionally substituted with at leastone substituent selected from the following group (a).

Further, in the case either one of Ra and Rb is a hydrogen atom, theother Ra and Rb represents a hydroxyl group, fluorine atom, chlorineatom, iodine atom, bromine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, Rx(Ry)N group (wherein, Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group), an alkyl group having1 to 12 carbon atoms substituted with at least one substituent selectedfrom the following group (a), unsubstituted alkyl group having 2 to 12carbon atoms, phenyl group optionally substituted with at least onesubstituent selected from the following group (a), naphthyl groupoptionally substituted with at least one substituent selected from thefollowing group (a), or heterocyclic group optionally substituted withat least one substituent selected from the following group (a), and aheterocyclic group does not form a spiro ring;

group (a):

hydroxyl group, alkyl group, alkenyl group, alkynyl group, fluorineatom, chlorine atom, iodine atom, bromine atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, and Rx(Ry)N group (wherein, Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group); and

group (b₁):

hydroxyl group, alkyl group having 2 to 12 carbon atoms, alkenyl group,alkynyl group, fluorine atom, chlorine atom, iodine atom, aromatichydrocarbon group, heterocyclic group, alkoxy group, guanidino group,alkylthio group, alkoxycarbonyl group, aryloxy group, arylthio group,acyl group, sulfonyl group, heterocyclyloxy group, heterocyclylthiogroup, amido group, ureido group, carboxyl group, carbamoyl group, oxogroup, sulfamoyl group, sulfo group, cyano group, nitro group, acyloxygroup, azido group, sulfonamido group, mercapto group,alkoxycarbonylamino group, and Rx(Ry)N group (wherein, Rx and Ryrespectively and independently represent a hydrogen atom, alkyl group,alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclicgroup)].

4. The oxazolone derivative according to any one of 1 to 3 above,wherein ring A in formula (I), (I′) or (I″) is a cyclohexylidene group.5. The oxazolone derivative according to any one of 1 to 4 above,wherein R¹, R^(1′) or R^(1″) in formula (I), (I′) or (I″) is aheterocyclic group optionally substituted with at least one substituentselected from the aforementioned group (a), a phenyl group substitutedwith at least one substituent selected from the aforementioned group(b₁), or an alkyl group having 1 to 12 carbon atoms substituted with anaromatic hydrocarbon group or heterocyclic group.

EFFECTS OF THE INVENTION

The oxazolone derivatives of the present invention are raw materialcompounds for producing novel cycloalkane carboxamide derivatives havingselective inhibition activity against cathepsin K, and are extremelyuseful raw material compounds since they can be easily produced fromcarboxylic acid derivatives using a known dehydration reaction.

BEST MODE FOR CARRYING OUT THE INVENTION

The oxazolone derivatives of the present invention are compoundsrepresented by the following formula (I), (I′) or (I″).

In formula (I), (I′) or (I″), examples of a saturated cyclic alkylidenegroup having 6 to 7 carbon atoms represented by ring A include acyclohexylidene group and a cycloheptylidene group, with acyclohexylidene group being preferable. R¹, R^(1′) and R^(1″) representan unsubstituted alkyl group having 3 to 12 carbon atoms, an alkyl grouphaving 1 to 12 carbon atoms substituted with at least one substituentselected from the aforementioned group (a) or group (a₁), an alkenylgroup having 2 to 12 carbon atoms optionally substituted with at leastone substituent selected from the aforementioned group (a), an alkynylgroup having 2 to 12 carbon atoms optionally substituted with at leastone substituent selected from the aforementioned group (a), a phenylgroup optionally substituted with at least one substituent selected fromthe aforementioned group (b) or (b₁), a naphthyl group optionallysubstituted with at least one substituent selected from theaforementioned group (a), a heterocyclic group optionally substitutedwith at least one substituent selected from the aforementioned group (a)or a group represented by Ra(Rb)CH—, wherein, in the case both Ra and Rbare not hydrogen atoms, Ra and Rb represent a hydroxyl group, fluorineatom, chlorine atom, iodine atom, bromine atom, aromatic hydrocarbongroup, heterocyclic group, alkoxy group, guanidino group, alkylthiogroup, alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, Rx(Ry)N group (wherein, Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group), an alkyl group having1 to 12 carbon atoms substituted with at least one substituent selectedfrom the following group (a), an unsubstituted alkyl group having 1 to12 carbon atoms, a phenyl group optionally substituted with at least onesubstituent selected from the following group (a), a naphthyl groupoptionally substituted with at least one substituent selected from thefollowing group (a), a heterocyclic group optionally substituted with atleast one substituent selected from the following group (a), an alkylgroup having 1 to 12 carbon atoms optionally substituted with at leastone substituent selected from the following group (a), an aromatichydrocarbon group optionally substituted with at least one substituentselected from the following group (a), or a heterocyclic groupoptionally substituted with at least one substituent selected from thefollowing group (a).

In addition, in the case either one of Ra and Rb is a hydrogen atom, theother Ra and Rb represents a hydroxyl group, fluorine atom, chlorineatom, iodine atom, bromine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, Rx(Ry)N group (wherein, Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group), an alkyl group having1 to 12 carbon atoms substituted with at least one substituent selectedfrom the following group (a), unsubstituted alkyl group having 2 to 12carbon atoms, phenyl group optionally substituted with at least onesubstituent selected from the following group (a), naphthyl groupoptionally substituted with at least one substituent selected from thefollowing group (a), or heterocyclic group optionally substituted withat least one substituent selected from the following group (a), and, isnot substituted with an amino group and a phenylmethoxycarbonyl group inthe case an alkyl group having 1 to 12 carbon atoms is a cyclohexylgroup, is not substituted with a heterocyclic group or1-carbonylaminocyclohexane carboxylic acid group in the case of a3-pentyl group, is not substituted with 3-oxa-1-azaspiro[4.5]dec-1-ene-4-one in the case of an n-butyl group, an unsubstitutedalkenyl group does not include a vinyl group and a propenyl group, andare not simultaneously substituted with a methyl group and a methoxygroup in the same benzene ring in the case of a phenyl group.

An unsubstituted alkyl group of R¹, R^(1′) or R^(1″) above may be any ofa linear, branched or cyclic alkyl group having 3 to 12 carbon atoms,examples of which include an n-propyl group, 2-propyl group, cyclopropylgroup, n-butyl group, 2-methylpropyl group, 2-butyl group,1,1-dimethylethyl group, cyclobutyl group, n-pentyl group, 3-methylbutylgroup, cyclopentyl group, 2,2-dimethylpropyl group, 1-methylcyclobutylgroup, cyclobutylmethyl group, n-hexyl group, 4-methylpentyl group,cyclohexyl group, 1-methylcyclopentyl group, cyclopentylmethyl group,(1-methylcyclobutyl)methyl group, n-heptyl group, 5-methylhexyl group,4,4-dimethylpentyl group, cycloheptyl group, cyclohexylmethyl group,(1-methylcyclopentyl)methyl group, n-octyl group, 6-methylheptyl group,5,5-dimethylhexyl group, (1-methylcyclohexyl)methyl group, n-nonylgroup, 7-methyloctyl group, 6,6-dimethylheptyl group, n-decyl group,8-methylnonyl group, n-dodecacyl group, 10-methylundecacyl group and9,9-dimethyldecacyl group.

A substituted alkyl group having 1 to 12 carbon atoms of R¹, R^(1′) orR^(1″) above may be any of a linear, branched or cyclic alkyl group,examples of which include the aforementioned alkyl groups as well as amethyl group, an ethyl group and the like. In addition, an alkyl groupof groups (a), (a₁) and (b) as well as Rx and Ry may be a linear,branched or cyclic alkyl group, examples of which include the same alkylgroups as those listed above.

An alkenyl group of R¹, R^(1′) or R^(1″) above may be any of a linear,branched or cyclic alkenyl group having 2 to 12 carbon atoms, examplesof which include a vinyl group, 1-propenyl group, 2-propenyl group,1-methylethenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenylgroup, 2-methyl-2-propenyl group, 1-propenyl group, 2-propenyl group,1-butenyl group, 2-butenyl group, 2-pentenyl group, 1-pentenyl group,1-hexenyl group and 2-hexenyl group. In addition, alkenyl groups of (a),(a₁), (b) and (b₁) as well as Rx and Ry are the same as those listedabove.

An alkynyl group of R¹, R^(1′) or R^(1″) above may be any of a linear,branched or cyclic alkynyl group having 2 to 12 carbon atoms, examplesof which include an ethynyl group, 1-propynyl group, 2-propynyl groupand 2-butynyl group. In addition, alkynyl groups of (a), (a₁), (b) and(b₁) as well as Rx and Ry are the same as those listed above.

An aromatic hydrocarbon group of (a), (a₁), (b) and (b₁) as well as Ra,Rb, Rx and Ry may be a monocyclic or polycyclic aromatic hydrocarbongroup having 6 to 18 carbon atoms, examples of which include a phenylgroup, naphthyl group and anthranyl group.

A heterocyclic group of R¹, R^(1′) or R^(1″) above is a 3- to 7-memberedring containing at least one heteroatom such as a nitrogen atom, oxygenatom or sulfur atom as a ring-composing atom, and these may be condensedwith heterocyclic rings, aliphatic ring and aromatic ring, examples ofwhich include a furanyl group, thienyl group, pyrrolyl group, pyrazolylgroup, thiazolyl group, oxazolyl group, isoxazolyl group, pyridinylgroup, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyranylgroup, indolyl group, benzofuranyl group, benzimidazolyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, pyrrolidinylgroup, piperidinyl group, piperazinyl group, morpholinyl group,indolinyl group and benzodioxolyl group. A furanyl group or morpholinylgroup is preferable. In addition, heterocyclic groups of (a), (a₁), (b)and (b₁) as well as Ra, Rb, Rx and Ry are the same as those listedabove.

Alkyl groups of alkoxy groups, alkylthio groups, alkoxycarbonyl groupsand alkoxycarbonylamino groups of the substituent groups or Ra and Rbare the same as the aforementioned alkyl groups having 1 to 12 carbonatoms, while aryl groups of aryloxy groups and arylthio groups are thesame as the aforementioned aromatic hydrocarbon groups having 6 to 18carbon atoms.

R¹, R^(1′) or R^(1″) is preferably a heterocyclic group optionallysubstituted with a substituent selected from the aforementioned group(a), a phenyl group substituted with a substituent selected from theaforementioned group (b¹), or an alkyl group having 1 to 12 carbon atomssubstituted with an aromatic hydrocarbon group or heterocyclic group.

Examples of a guanidino group, acyl group, sulfonyl group,heterocyclyloxy group, heterocyclylthio group, amido group, ureidogroup, carbamoyl group, sulfamoyl group, acyloxy group, sulfonamidogroup and alkoxycarbonyl amino group described in the aforementionedsubstituent groups include the groups indicated below.

Among the groups exemplified above, R⁹ to R¹², R¹⁷ to R²¹, R²³ to R²⁵,R²⁸ and 230 represent a hydrogen atom, substituted or unsubstitutedalkyl group, substituted or unsubstituted alkenyl group, substituted orunsubstituted alkynyl group, substituted or unsubstituted aromatichydrocarbon group, or substituted or unsubstituted heterocyclic group.R¹³, R¹⁴, R²², R²⁶, R²⁷ and R²⁹ represent a substituted or unsubstitutedalkyl group, substituted or unsubstituted alkenyl group, substituted orunsubstituted alkynyl group, substituted or unsubstituted aromatichydrocarbon group, or substituted or unsubstituted heterocyclic group.R¹⁵ and R¹⁶ represent a substituted or unsubstituted heterocyclic group.In addition, examples of substituents of these substituted alkyl groups,substituted alkenyl groups, substituted alkynyl groups, substitutedaromatic hydrocarbon groups and substituted heterocyclic groups includethe same substituents as the substituents of these groups listed for R¹in 1 above.

Specific examples of oxazolone derivatives represented by theaforementioned formula (I) of the present invention include thefollowing compounds:

-   2-phenylmethyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-phenylethyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-biphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[(RS)-2,3-tetrahydrobenzofuran-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(6-benzothiazolyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1,3-benzoxol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-benzofuranyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-pyridiny)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-ethoxy-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-pyrazinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(5-methylisoxazol-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cyclopentyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(5-methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-methyl-2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-methyl-1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1H-indol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-cyclopentenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(6-hydroxy-2-pyridiny)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(furanyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-[(2-propoxy)carbonyl]piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-(ethoxycarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[1-(2-furanylcarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[[(2-furanylcarbonyl)amino]methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[(benzoylamino)methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(1-propyl)piperazin-1-yl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-furyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cyclohexyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-propyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-acetyl-piperidin-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(2-[1,4-b]piperidine]-1′-yl-4-thiazolyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(1,1-dimethylethyl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-([1,1′-biphenyl]-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(4-pyridiny)-4-thiazolyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-aminophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-morpholinyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(5-bromo-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(4-methyl-1-piperazinyl)carbonyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(dimethylamino)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-ethynylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4′-(dimethylamino)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-methyl-1-piperazinyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[1-(2-hydroxyethyl)-4-piperidinyl]oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[(1-methyl-4-piperidinyl)oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[methyl(1-methyl-3-pyrrolidinyl)amino][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[4-(1,1-dimethylethyl)-1-piperidinyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(1-piperazinylsulfonyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(4-fluoro-4-piperidinyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[4-(2,2,2-trifluoroethyl)-1-piperazinyl]sulfonyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[(1-methyl-3-piperidinyl)oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[[1-(2-methoxyethyl)-4-piperidinyl]oxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4′-[[(2S)-1-methyl-2-pyrrolidinyl]methoxy][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-[4-[(1,1-dimethylethyl)amino]-1-piperidinyl][1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4′-(5-isoxazolyl)[1,1′-biphenyl]-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-morpholinylmethyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[3-(dimethylamino)-1-pyrrolidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-methyl-1-piperazinylmethyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(1,4-dimethyl-4-piperidinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(1-methyl-4-piperidinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[(3R)-3-amino-1-pyrrolidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-(4-piperidinyloxy)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-[2-(4-morpholinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-[(1-methylethyl)amino]-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[methyl(4-methyl-1-piperazinyl)amino]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-[methyl(1-methylethyl)amino]-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(tetrahydro-2H-pyran-4-yl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[2-[4-(2-methoxyethyl)-1-piperazinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(4-morpholinyl)-1-propynyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-cycloheptyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]    dec-1-en-4-one,-   2-cyclopropyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(diethylamino)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(1-methyl-4-piperazinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(1-piperazinyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,-   2-[4-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(trifluoromethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-pyridiny)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[2-(trifluoromethoxy)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(3-methylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[4-[(methoxymethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]    dec-1-en-4-one,    2-(3-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-chlorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-cyanophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(phenoxymethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-chlorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-thienylmethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2-methylphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-hydroxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-[3-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(4-methyl-1,2,3-thiadiazol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one,    2-(2,5-dimethyl-3-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one.

Oxazolone derivatives represented by formula (I) of the presentinvention can be produced by ring-closing a carboxylic acid derivativerepresented by structural formula (VI), and ester thereof, by ahydrogenation reaction as shown in the following process drawing. Inaddition, the carboxylic acid derivative of structural formula (VI) isproduced from a raw material amino acid (II) or amino acid esterderivative (III) by going through each of the respective steps.

(In the above formulas, R¹ and ring A are as previously defined informula (I) above, X represents a hydroxyl group or leaving group, R²represents a substituted or unsubstituted alkyl group, substituted orunsubstituted alkenyl group, substituted or unsubstituted alkynyl group,substituted or unsubstituted aromatic hydrocarbon group or substitutedor unsubstituted heterocyclic group, and R³ and R⁸ represent asubstituted or unsubstituted alkyl group having 1 to 6 carbon atoms.)

The following provides an explanation of the production process ofoxazolone derivatives represented by formula (I) of the presentinvention, and each of the steps for producing a cycloalkylcarbonylaminoaldehyde derivative represented by formula (XIII), having an action thatselectively inhibits cathepsin K, from these oxazolone derivatives orprecursors thereof in the form of carboxylic acids or carboxylic acidderivatives represented by formula (IV).

Step 1:

This step is a step for producing a cycloalkylcarboxylic acid derivativerepresented by general formula (VI) above by condensing an amino acidrepresented by formula (II) above and a carboxylic acid derivativerepresented by formula (IV) above. Examples of carboxylic acidderivatives used include acid halides, active esters and acidanhydrides. In addition, the reaction of this step can be carried out byadding a base as necessary. Examples of bases that can be used includepyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, sodium carbonate,potassium carbonate, sodium bicarbonate, sodium hydroxide and potassiumhydroxide. This step is preferably carried out in a solvent, examples ofsolvents that can be used include organic solvents such as methylenechloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene,toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran,dioxane, diethyl ether, isopropyl ether or dimethoxyethane, and water,and a mixed solvent of organic solvent and water can be used asnecessary. The reaction is normally carried out at a reactiontemperature within the range of −30 to 200° C., and can be preferablyallowed to proceed within the range of −15 to 100° C.

Step 2:

This step is a step for producing a cycloalkyl ester derivativerepresented by formula (V) above by a condensation reaction of an aminoacid ester represented by formula (III) above and a carboxylic acid orcarboxylic acid derivative represented by formula (IV) above. Examplesof carboxylic acid derivatives that can be used include acid halides,active esters and acid anhydrides. In addition, the reaction of thisstep can be carried out by adding a condensation agent or base asnecessary. Examples of condensation agents that can be used includedicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide and carbonyldiimidazole. Here, anactivating agent such as 1-hydroxybenzotriazole can also be added asnecessary. Examples of bases that can be used include pyridine,triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, sodium carbonate, potassium carbonate and sodiumbicarbonate.

This step is preferably carried out in a solvent, examples of solventsthat can be used include organic solvents such as methylene chloride,chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene,xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane,diethyl ether, isopropyl ether and dimethoxyethane, and water, and amixed solvent of organic solvent and water can be used as necessary. Thereaction temperature is normally within the range of −30 to 200° C. andcan be preferably allowed to proceed within the range of −15 to 100° C.

Step 3:

This step is a step for producing a compound represented by formula (VI)above by hydrolyzing a cycloalkyl ester derivative represented byformula (V) above or hydrogenating a cycloalkyl ester derivativerepresented by formula (V) above by a catalytic reduction using a metalcatalyst. Hydrolysis can be carried out in the presence of acid or base.Examples of acids that can be used include hydrochloric acid, sulfuricacid, nitric acid and acetic acid. Examples of bases that can be usedinclude sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate and potassium carbonate. The hydrolysis reaction is preferablycarried out in water or a mixed solvent of organic solvent and water,and examples of organic solvents that can be used include methanol,ethanol, isopropyl alcohol, tetrahydrofuran and dimethoxyethane. Thereaction is normally carried out at a reaction temperature within therange of −20 to 200° C. and can be preferably allowed to proceed withinthe range of 0 to 180° C. In addition, examples of metal catalysts thatcan be used in the catalytic hydrogenation reaction include platinum,palladium, nickel, rhodium, ruthenium and copper. Catalytic reduction ispreferably carried out in a solvent, and examples of solvents that canbe used include methanol, ethanol, isopropyl alcohol, isopropyl ether,tetrahydrofuran, benzene, toluene, xylene, dimethylformamide, dioxaneand water. The reaction is normally carried out within the range of −50to 200° C. and can be preferably allowed to proceed within the range of10 to 100° C.

Examples of carboxylic acids or carboxylic acid derivatives representedby formula (IV) above include the compounds listed below.

Carboxylic acids: acetic acid, isobutyric acid, acrylic acid, propionicacid, cyclohexane carboxylic acid, benzoic acid, cinnamic acid, 2-furancarboxylic acid, nicotinic acid, tetrahydrofuran-2-carboxylic acid,1-acetyl-piperidine-2-carboxylic acid, 2-pyrrole carboxylic acid,5-indole carboxylic acid;

Acid halides: acetyl chloride, benzoyl chloride, pivaloyl chloride,2-furan carbonyl chloride, 4-morpholine carbonyl chloride, 2-thiophenecarbonyl chloride;

Active esters: 1-acetylimidazole, benzoic acid p-nitrophenyl esters,benzoic acid N-hydroxysuccinimide esters, benzoic acid1-hydroxybenzotriazole esters; and

Acid anhydrides: acid anhydrides of benzoic acid and methyl carbonate,acid anhydrides of benzoic acid and isobutyl carbonate, acid anhydridesof benzoic acid and pivalic acid, acid anhydrides of benzoic acid andmethanesulfonic acid.

Step 4:

This step is a step for producing an oxazolone derivative represented byformula (I) above by ring-closing a cycloalkylcarboxylic acid derivativerepresented by formula (VI) abode by a dehydration reaction.

The dehydration reaction of this step is preferably carried out in thepresence of a condensation agent, halogenating agent, acid, acidanhydride or acid chloride and the like, and examples of condensationagents that can be used include dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,diisopropylcarbodiimide and carbonyldiimidazole. Examples ofhalogenating agents that can be used include chlorine, bromine, iodine,phosphorous pentachloride, thionyl chloride, oxalyl chloride and thionylbromide. Examples of acids that can be used include acetic acid,sulfuric acid, hydrochloric acid, methanesulfonic acid andtoluenesulfonic acid. Examples of acid anhydrides that can be usedinclude acetic anhydride, methanesulfonic anhydride, toluenesulfonicanhydride and trifluoromethanesulfonic anhydride. Examples of acidchlorides that can be used include acetyl chloride, pivaloyl chloride,methanesulfonyl chloride, toluenesulfonyl chloride, methylchloroformate, ethyl chloroformate, propyl chloroformate and isobutylchloroformate.

In addition, the reaction of this step can also be carried out by addinga base as necessary, and examples of bases that can be used includepyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, sodium carbonate,potassium carbonate and sodium bicarbonate.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, chloroform,dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethylether, diisopropyl ether and dimethoxyethane. The reaction is normallycarried out at a reaction temperature within the range of −30 to 200° C.and can be preferably allowed to proceed within the range of 0 to 100°C.

Step 5:

This step is a step for producing a cycloalkylcarbonyl-amino acidderivative represented by the formula (X) above by reacting an oxazolonederivative represented by formula (I) above with an amino acidderivative represented by formula (VII) above.

This step can be carried out in the presence of a base and in thepresence or absence of a solvent, and examples of solvents that can beused include methylene chloride, chloroform, dichloroethane, ethylacetate, acetone, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropylether, dimethoxyethane, dimethylsulfoxide, methanol, ethanol and2-propanol. In addition, examples of bases that can be used includepyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, sodium carbonate,potassium carbonate, sodium bicarbonate, sodium hydroxide and potassiumhydroxide. The reaction is normally carried out at a reactiontemperature within the range of −30 to 200° C. and can be preferablyallowed to proceed within the range of 20 to 200° C.

Step 6:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by reacting an oxazolonederivative represented by formula (I) above with an amino alcoholderivative represented by formula (VIII) above.

This step can be carried out in the presence or absence of solvent, andexamples of solvents that can be used include methylene chloride,chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene,xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane,diethyl ether, diisopropyl ether, dimethoxyethane, dimethylsulfoxide,methanol, ethanol and 2-propanol. In addition, in this step, a base canbe added as necessary. Examples of bases that can be used includepyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine and N-methylmorpholine. The reaction isnormally carried out at a reaction temperature within the range of −30to 200° C. and can be preferably allowed to proceed within the range of20 to 200° C.

Step 7:

This step is a step for producing a cycloalkylcarbonylamino acid esterderivative represented by formula (XII) above by reacting an oxazolonederivative represented by formula (I) above with an amino acid esterderivative represented by formula (IX) above.

This step can be carried out in the presence or absence of solvent, andexamples of solvents that can be used include methylene chloride,chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene,xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane,diethyl ether, diisopropyl ether, dimethoxyethane, dimethylsulfoxide,methanol, ethanol and 2-propanol. In addition, in this step, a base canbe added as necessary. Examples of bases that can be used includepyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine and N-methylmorpholine. The reaction isnormally carried out at a reaction temperature within the range of −30to 200° C. and can be preferably allowed to proceed within the range of20 to 200° C.

Step 8:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by carrying out a reductionreaction after activating a cycloalkylcarbonylamino acid represented byformula (X) above by a mixed acid anhydride method.

Examples of acid chlorides that can be used in the reaction for forminga mixed acid anhydride in this step include pivaloyl chloride, isobutylchloroformate, methyl chloroformate, ethyl chloroformate,methanesulfonyl chloride and toluenesulfonyl chloride. Examples of basesthat can be used include pyridine, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine andN-methylmorpholine.

This reaction is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, chloroform,dichloroethane, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl etherand dimethoxyethane.

The reaction is normally carried out at a reaction temperature withinthe range of −50 to 200° C. and can be preferably allowed to proceedwithin the range of −20 to 50° C.

In addition, examples of reducing agents that can be used in this stepinclude sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and sodium dihydro-bis(2-methoxyethoxy)aluminate(Red-Al).

This reduction reaction is preferably carried out in a solvent, andexamples of solvents that can be used include methylene chloride,chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropylether, dimethoxyethane, ethanol, 2-propanol and water. The reaction isnormally carried out at a reaction temperature within the range of −30to 200° C. and can be preferably allowed to proceed within the range of−20 to 80° C.

Step 9:

This step is a step for producing a cycloalkylcarbonylamino alcoholderivative represented by formula (XI) above by reducing acycloalkylcarbonylamino acid ester derivative represented by formula(XII) above.

Examples of reducing agents that can be used in this step include sodiumborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, andRed-Al.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, chloroform,dichloroethane, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl etherand dimethoxyethane.

The reaction is normally carried out at a reaction temperature withinthe range of −100 to 200° C. and can be preferably allowed to proceedwithin the range of −80 to 100° C.

Step 10:

This step is a step for producing a cycloalkylcarbonylamino aldehydederivative represented by formula (XIII) above by oxidizing acycloalkylcarbonylamino alcohol derivative represented by formula (XI)above.

The oxidation reaction used in this step can use activated DMSO(dimethylsulfoxide) oxidation. Examples of electrophilic activatingreagents used here include dicyclohexylcarbodiimide, phosphorouspentoxide, pyridine-sulfur trioxide complex, acetic anhydride, silver(II) acetate and oxalyl chloride. A hydrogen donor such as phosphoricacid, trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoricacid or pyridine-trifluoroacetic acid can also be added in this step asnecessary. In addition, an amine such as triethylamine,N,N-diisopropylethylamine or N-methylmorpholine can also be added asnecessary.

This step can be carried out in dimethylsulfoxide, and a solvent such asmethylene chloride, chloroform, dichloroethane, toluene, acetone ortetrahydrofuran can also be added as necessary.

The reaction is normally carried out at a reaction temperature withinthe range of −80 to 200° C. and can be preferably allowed to proceedwithin the range of −40 to 40° C.

In addition, in this step, an oxidation reaction can also be carried outby preparing an active species having a structure resembling anactivated DMSO reaction from a sulfide and halogenating agent. Examplesof sulfides that can be used in this step include dimethyl sulfide andmethyl phenyl sulfide. Examples of halogenating agents that can be usedinclude N-chlorosuccinimide and chlorine.

In this step, an amine such as triethylamine, N,N-diisopropylethylamine,N-methylmorpholine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can alsobe added as necessary.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, chloroform,dichloroethane, toluene and tetrahydrofuran.

The reaction is normally carried out at a reaction temperature withinthe range of −80 to 200° C. and can be preferably allowed to proceedwithin the range of −40 to 40° C.

In addition, oxidation can also be carried out in this step using ahypervalent iodine compound reagent. Examples of hypervalent iodinecompounds used in this step include Dess-Martin reagent(1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) and IBX(1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide).

A base such as pyridine or sodium bicarbonate can be added in this stepas necessary.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, chloroform,dichloroethane, benzene, toluene, xylene, dimethylformamide,acetonitrile, tetrahydrofuran, dioxane and dimethoxyethane.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

In addition, this step can also be carried out using oxidation(Oppenauer's oxidation) with aluminum alkoxide and a hydrogen acceptor.Examples of aluminum alkoxides that can be used include aluminumisopropoxide and aluminum t-butoxide.

Examples of hydrogen acceptors that can be used include benzoquinone,benzophenone, acetone, cyclohexanone and benzaldehyde.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include benzene, toluene and xylene.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 150° C.

In addition, this step can also be carried out using an oxidationreaction with tetrapropylammonium perruthenate (TPAP).

N-methylmorpholine-N-oxide or molecular oxygen can be used as theoxidizing agent.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include methylene chloride, acetonitrile andtoluene.

A molecular sieve can be added in this step as necessary.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

In addition, this step can also use an oxidation reaction with2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or derivativethereof.

Examples of oxidizing agents that can be used include hypochlorite,bromite and N-chlorosuccinimide.

This step is preferably carried out in a solvent, and examples ofsolvents that can be used include dimethylsulfoxide,N,N-dimethylformamide, methylene chloride, acetonitrile, toluene andethyl acetate.

In addition, sodium bromide or water can also be added in this step asnecessary.

The reaction is normally carried out at a reaction temperature withinthe range of −20 to 200° C. and can be preferably allowed to proceedwithin the range of 0 to 40° C.

Examples of cycloalkylcarboxylic acid derivatives represented by formula(VI) which are precursors of an oxazolone derivative represented byformula (I) of the present invention include the compounds listed below.

-   1-[(phenylacetyl)amino]cyclohexanecarboxylic acid,    1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylic acid,    1-(benzoylamino)cyclohexanecarboxylic acid,    1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(1-naphthylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[[(RS)-2,3-tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylic    acid, 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic    acid, 1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(6-hydroxy-3-pyridiny)carbonyl]amino]cyclohexanecarboxylic acid,    1-[(2-thienylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(2-pyridinycarbonyl)amino]cyclohexanecarboxylic acid,-   1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(3-ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid,    1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(3-methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[(3-pyridinycarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic    acid, 1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid,    1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid,    1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid,-   1-[(4-pyridinycarbonyl)amino]cyclohexanecarboxylic acid,    1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(6-hydroxy-2-pyridiny)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(2-hydroxy-3-pyridiny)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[(6-hydroxy-3-pyridiny)carbonyl]amino]cyclohexanecarboxylic acid,    1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylic    acid,    1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic    acid, 1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid,    1-[[(2-oxo-2H-pyran-5-yl)carbonyl]amino]cyclohexanecarboxylic acid,    1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid,    1-[[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid hydrochloride,-   [[(2,3-dihydro-2-oxo-5-benzoxazole)carbonyl]amino]cyclohexanecarboxylic    acid,    [[(2,3-dihydro-1,4-benzodioxin-6-yl)carbonyl]amino]cyclohexanecarboxylic    acid,    [[(2,4-dioxo-3-thiazolidinyl)acetyl]amino]cyclohexanecarboxylic    acid, [(1-oxo-3-phenyl-2-propenyl)amino]cyclohexanecarboxylic acid,    [[1-oxo-3-(2-chlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-chlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dichlorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-bromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-bromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dibromophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[(1-oxo-3-(2-fluorophenyl)-2-propenyl)amino]cyclohexanecarboxylic    acid,-   [[1-oxo-3-(2-iodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(4-fluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(difluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-iodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(diiodophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(trifluorophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(3-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-methylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dimethylphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(2-methoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(4-methoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dimethoxyphenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,-   [[1-oxo-3-(nitrophenyl)-2-propenyl]amino]cyclohexanecarboxylic acid,    [[1-oxo-3-(dinitrophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid,    [[oxo-3-(acetaminophenyl)-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(2-pyridiny)-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-cyclohexyl-2-propenyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-cyclopentyl-2-propenyl]amino]cyclohexanecarboxylic    acid, [(1-oxo-3-phenyl-2-propynyl)amino]cyclohexanecarboxylic acid,    [[1-oxo-3-(fluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(chlorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(bromophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid, [[1-oxo-3-(iodophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(difluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(dibromophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(diiodophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,    [[1-oxo-3-(trifluorophenyl)-2-propynyl]amino]cyclohexanecarboxylic    acid,-   [(1-oxo-3-cyclohexyl-2-propynyl)amino]cyclohexanecarboxylic acid,    [(1-oxo-3-cyclopentyl-2-propynyl)amino]cyclohexanecarboxylic acid,    [[3-(2-furanyl)-1-oxo-2-propynyl]amino]cyclohexanecarboxylic acid,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid acetate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid hydrobromide,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid acetate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid benzensulfonate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid toluenesulfonate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid phthalate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid fumarate,    1-[[4-[4-(1-propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylic    acid citrate.

As has been described above, cycloalkylcarbonylamino aldehydederivatives having an action that selectively inhibits cathepsin K canbe produced by going through each of the reaction steps described aboveby using the oxazolone derivatives of the present invention. Compoundsused in these reaction steps are able to form a salt with an acid in thecase of having a basic site in a molecular thereof, and examples ofinorganic acids include hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid and hydrobromic acid. In addition, examples of organicacids include acetic acid, propionic acid, benzoic acid, oxalic acid,malonic acid, succinic acid, phthalic acid, glycolic acid, lactic acid,glyceric acid, malic acid, tartaric acid, gallic acid, citric acid,maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acidand toluenesulfonic acid.

In addition, in the case of having an acidic site in a molecule thereof,a salt can be formed with, for example, an alkaline metal such aslithium, sodium or potassium, an alkaline earth metal such as magnesiumor calcium, aluminum or zinc. Moreover, a salt can also be formed withan organic base, and examples of these organic bases include primaryamines such as methylamine, ethylamine or aniline, secondary amines suchas diethylamine, pyrrolidine, piperidine, morpholine, piperazine ordicyclohexylamine, tertiary amines such as trimethylamine,triethylamine, N,N-diisopropylethylamine or pyridine, and ammonia.

The selective inhibitory action against cathepsin K of thesecycloalkylcarbonylamino aldehyde derivatives derived from the oxazolonederivatives of the present invention is clear from the text examples tobe described later. Accordingly, the oxazolone derivatives of thepresent invention are extremely useful compounds for use as synthesisraw material compounds of these cycloalkylcarbonylamino aldehydederivatives.

Although the following provides a more detailed explanation of thepresent invention through reference examples and examples, the presentinvention is not limited to these examples provided they do not exceedthe gist thereof.

Furthermore, “%” refers to “% by weight” unless specifically indicatedotherwise.

Synthesis examples of carboxylic acids represented by formula (VI) aboveand esters thereof for producing the oxazolone derivatives of thepresent invention are indicated in the following Reference Examples 1 to131 and 152 to 164. In addition, production examples ofcycloalkylcarbonylamino aldehyde derivatives derived from the oxazolonederivatives of the present invention, and intermediates of said aldehydederivatives, are indicated as reference examples.

REFERENCE EXAMPLE 1 1-[(Phenylacetyl)amino]cyclohexanecarboxylic acidphenylmethyl ester

1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 mlof tetrahydrofuran, 1.55 g (10 mmol) of phenylacetyl chloride was addeddropwise thereto under ice-cooling, and the mixture was stirredovernight. The reaction solution was concentrated under reducedpressure, ethyl acetate was added thereto, the mixture was successivelywashed with water, a 10% aqueous potassium hydrogensulfate solution, asaturated aqueous sodium hydrogencarbonate solution and saturated brine,followed by drying with anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, the residue was purified by silicagel chromatography to obtain 3.21 g (91%) of the title compound.

1H-NMR (CDCl₃, δ): 1.10-1.23 (3H, m), 1.50-1.58 (3H, m), 1.74-1.80 (2H,m), 1.95-1.98 (2H, m), 3.57 (2H, s), 5.12 (2H, s), 5.48 (1H, br-s),7.24-7.38 (10H, m)

REFERENCE EXAMPLE 2 1-[(Phenylacetyl)amino]cyclohexanecarboxylic acid

2.69 g (9.1 mmol) of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acidphenylmethyl ester obtained in Reference Example 1 was dissolved in 100ml of methanol, 300 mg of 10% palladium-carbon was added thereto, andthe mixture was stirred under a hydrogen atmosphere at room temperatureovernight. After the reaction solution was filtered, the filtrate wasconcentrated under reduced pressure to obtain 1.96 g (98%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.01-1.10 (2H, m), 1.18-1.26 (1H, m), 1.49-1.59 (3H,m), 1.75-1.82 (2H, m), 1.97-2.00 (2H, m), 3.66 (2H, s), 5.67 (1H, br-s),7.29-7.34 (3H, m), 7.37-7.40 (2H, m)

REFERENCE EXAMPLE 3 1-[(1-Oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.68 g (10 mmol) of 3-phenylpropionyl chloride was used instead ofphenylacetyl chloride in the process according to Reference Example 1 toobtain 3.47 g (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.19-1.26 (3H, m), 1.50-1.61 (3H, m), 1.78-1.84 (2H,m), 1.96-2.05 (2H, m), 2.50 (2H, t, J=7 Hz), 2.93 (2H, t, J=7 Hz), 5.13(2H, s), 5.45 (1H, br-s), 7.18-7.21 (4H, m), 7.26-7.37 (6H, m)

REFERENCE EXAMPLE 4 1-[(1-Oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid

3.47 g (9.5 mmol) of1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid phenylmethyl ester in the process according to Reference Example 2to obtain 2.35 g (90%) of the title compound.

1H-NMR (CDCl₃, δ): 1.16-1.25 (3H, m), 1.48-1.51 (1H, m), 1.52-1.62 (2H,m), 1.84-1.97 (4H, m), 2.62 (2H, t, J=7 Hz), 3.00 (2H, t, J=7 Hz), 5.43(1H, br-s), 7.21-7.26 (3H, m), 7.29-7.33 (2H, m)

REFERENCE EXAMPLE 5 1-(Benzoylamino)cyclohexanecarboxylic acidphenylmethyl ester

1.41 g (10 mmol) of benzoyl chloride was used instead of phenylacetylchloride in the process according to Reference Example 1 to obtain 3.39g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.33-1.40 (1H, m), 1.45-1.54 (2H, m), 1.62-1.76 (3H,m), 1.93-1.99 (2H, m), 2.19-2.22 (2H, m), 5.17 (2H, s), 6.25 (1H, br-s),7.25-7.32 (4H, m), 7.41-7.45 (3H, m), 7.49-7.52 (1H, m), 7.75-7.77 (2H,m)

REFERENCE EXAMPLE 6 1-(Benzoylamino)cyclohexanecarboxylic acid

3.39 g (10 mmol) of 1-(benzoylamino)cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 2.44 g (99%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.38-1.55 (3H, m), 1.67-1.71 (1H, m), 1.75-1.79 (2H,m), 1.98-2.04 (2H, m), 2.24-2.27 (2H, m), 6.26 (1H, br-s), 7.46 (1H, td,J=7 Hz, 1 Hz), 7.48 (1H, td, J=7 Hz, 1 Hz), 7.57 (1H, td, 7 Hz, 1 Hz),7.79-7.82 (2H, m)

REFERENCE EXAMPLE 7 1-[(4-Biphenylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

2.11 g (11 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 2.33 g (10 mmol) of1-aminocyclohexanecarboxylic acid phenylmethyl ester, 1.68 g (11 mmol)of 1-hydroxybenzotriazole and 3.23 g (10 mmol) of 4-biphenylcarboxylicacid in 120 ml of methylene chloride under ice-cooling. After themixture was stirred at room temperature overnight, the reaction solutionwas concentrated under reduced pressure, ethyl acetate was addedthereto, and the mixture was successively washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel chromatographyto obtain 3.51 g (85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.38-1.41 (1H, m), 1.51-1.61 (2H, m), 1.66-1.80 (3H,m), 1.95-2.05 (2H, m), 2.23-2.31 (2H, m), 5.20 (2H, s), 6.38 (1H, br-s),7.24-7.34 (7H, m), 7.55-7.60 (2H, m), 7.81 (1H, dd, J=8 Hz, 1 Hz),7.87-7.91 (3H, m), 8.26 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 8 1-[(4-Biphenylcarbonyl)amino]cyclohexanecarboxylicacid

3.51 g (8.5 mmol) of 1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 2.75 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.48 (1H, m), 1.48-1.60 (2H, m), 1.66-1.73 (1H,m), 1.73-1.82 (2H, m), 2.00-2.10 (2H, m), 2.27-2.35 (2H, m), 6.32 (1H,br-s), 7.39-7.43 (1H, m), 7.46-7.49 (2H, m), 7.61-7.66 (2H, m),7.68-7.70 (2H, m), 7.87-7.89 (2H, m)

REFERENCE EXAMPLE 9 1-[(2-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.28 g (7.4 mmol) of 2-naphthoeic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference Example7 to obtain 2.12 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.48-1.61 (2H, m), 1.64-1.78 (3H,m), 1.95-2.01 (2H, m), 2.21-2.24 (2H, m), 5.19 (2H, s), 6.27 (1H, br-s),7.27-7.36 (3H, m), 7.40 (1H, td, J=7 Hz, 1 Hz), 7.46-7.49 (2H, m),7.61-7.63 (2H, m), 7.65-7.67 (2H, m), 7.83-7.85 (2H, m)

REFERENCE EXAMPLE 10 1-[(2-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid

2.12 g (5.5 mmol) of 1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 1.63 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.41-1.45 (1H, m), 1.52-1.60 (2H, m), 1.70-1.74 (1H,m), 1.77-1.82 (2H, m), 2.03-2.09 (2H, m), 2.29-2.32 (2H, m), 6.41 (1H,br-s), 7.56-7.63 (2H, m), 7.83 (1H, dd, J=8 Hz, 2 Hz), 7.89-7.96 (3H,m), 8.33 (1H, s)

REFERENCE EXAMPLE 11 1-[(1-Naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

1.72 g (10 mmol) of 1-naphthoeic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference Example7 to obtain 3.87 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.42 (1H, m), 1.45-1.60 (2H, m), 1.65-1.71 (1H,m), 1.71-1.80 (2H, m), 1.98-2.05 (2H, m), 2.24-2.32 (2H, m), 5.26 (2H,s), 6.10 (1H, br-s), 7.32-7.37 (3H, m), 7.40-7.45 (4H, m), 7.48-7.52(1H, m), 7.57 (1H, dd, J=7 Hz, 1 Hz), 7.85 (1H, dd, J=7 Hz, 1 Hz), 7.91(1H, dd, J=7 Hz, 1 Hz), 8.25 (1H, dd, J=7 Hz, 1 Hz)

REFERENCE EXAMPLE 121-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

12.22 g (75.4 mmol) of benzofuran-2-carboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference Example7 to obtain 21.3 g (75%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26-1.42 (1H, m), 1.50-1.61 (2H, m), 1.64-1.77 (3H,m), 1.95-2.04 (2H, m), 2.21-2.28 (2H, m), 5.19 (2H, s), 6.77 (1H, br-s),7.25-7.34 (6H, m), 7.44 (1H, td, J=8 Hz, 2 Hz), 7.52 (1H, dd, J=8 Hz, 2Hz), 7.57 (1H, dd, J=8 Hz, 2 Hz), 7.68 (1H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 131-[[[(RS)-2,3-Tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylicacid

1.5 g of 10% palladium-carbon was added to a solution of 15 g (40 mmol)of 1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester in 300 ml of 2-propanol, and the mixture was stirredunder a hydrogen atmosphere at 60° C. for 20 hours. After the reactionsolution was filtered, the filtrate was concentrated under reducedpressure to obtain 11.57 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.07-1.19 (1H, m), 1.21-1.36 (2H, m), 1.50-1.63 (2H,m), 1.65-1.71 (1H, m), 1.80-1.88 (1H, m), 1.89-1.95 (1H, m), 2.04-2.15(2H, m), 3.42 (1H, dd, J=17 Hz, 7 Hz), 3.60 (1H, dd, J=17 Hz, 7 Hz),5.18 (1H, dd, J=7 Hz, 7 Hz), 6.84 (1H, br-s), 6.91 (1H, d, J=8 Hz), 6.96(1H, dd, J=8 Hz, 1 Hz), 7.18 (1H, td, J=8 Hz, 1 Hz), 7.22 (1H, dd, J=8Hz, 1 Hz)

REFERENCE EXAMPLE 14 1-[(2-Furanylcarbonyl)amino]cyclohexanecarboxylicacid

71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to 20 g(0.5 mol) of sodium hydroxide in 250 ml of aqueous solution, and themixture was stirred at 80° C. for 2 hours. The mixture solution wascooled by ice-water, 71.8 g (0.2 mol) of 2-furancarbonyl chloride and 24g (0.6 mol) of sodium hydroxide in 100 ml of aqueous solution weresimultaneously added thereto over approximately 1 hour. The reactionsolution was slowly returned to room temperature and stirred overnight.80 ml of ethyl acetate was added to the reaction solution and after themixture was stirred for 1 hour, the insolubles were removed byfiltration. The aqueous layer was separately collected, and 49 ml ofconcentrated hydrochloric acid was added thereto under ice-cooling. Theprecipitated crystal was collected by filtration and dried under reducedpressure to obtain 112.6 g (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.41 (1H, m), 1.48-1.53 (2H, m), 1.64-1.67 (1H,m), 1.71-1.76 (2H, m), 1.96-2.02 (2H, m), 2.20-2.24 (2H, m), 6.48 (1H,br-s), 6.55 (1H, dd, J=4 Hz, 2 Hz), 7.19 (1H, dd, J=4 Hz, 1 Hz), 7.50(1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 15 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 98.8 g (500 mmol) of1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g(550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 mlof methylene chloride under ice-cooling. After the mixture was stirredat room temperature overnight, the reaction solution was concentratedunder reduced pressure. Ethyl acetate was added to the residue, and themixture was successively washed with water, a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with anhydrous sodiumsulfate. After the solvent was distilled off under reduced pressure, theobtained crystal was washed with diisopropyl ether to obtain 114 g (91%)of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m), 1.62-1.73 (3H,m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s),6.23 (1H, dd, J=2 Hz, 1 Hz), 7.44 (1H, dd, J=2 Hz, 1 Hz), 7.94 (1H, dd,J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 16 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylicacid

450 ml of 2N aqueous sodium hydroxide solution was added to a solutionof 75.4 g (300 mmol) of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester in450 ml of tetrahydrofuran, and the mixture was heated under reflux for 3hours. After ether was added to the reaction solution to wash it, theaqueous layer was neutralized by concentrated hydrochloric acid andextracted with ethyl acetate. After the obtained organic layer waswashed with saturated brine, it was dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to obtain 68.8 g(97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.50 (3H, m), 1.58-1.64 (1H, m), 1.68-1.80 (2H,m), 1.98-2.05 (2H, m), 2.14-2.23 (2H, m), 5.87 (1H, s), 6.63 (1H, d, J=2Hz), 7.49 (1H, d, J=2 Hz), 8.00 (1H, s)

REFERENCE EXAMPLE 171-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidmethyl ester

80 g (362 mmol) of 2-furanacrylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 89 g (89%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.39 (1H, m), 1.40-1.51 (2H, m), 1.58-1.71 (3H,m), 1.88-1.95 (2H, m), 2.05-2.14 (2H, m), 3.73 (3H, s), 5.67 (1H, br-s),6.35 (1H, d, J=16 Hz), 6.45 (1H, dd, J=3H, z, 2 Hz), 6.54 (1H, d, J=3Hz), 7.37 (1H, d, J=16 Hz), 7.40 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 181-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acid

44.9 g (162 mmol) of1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 37.5 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.85 (6H, m), 1.96-2.05 (2H, m), 2.15-2.18 (2H,m), 5.66 (1H, br-s), 6.36 (1H, d, J=15 Hz), 6.49 (1H, dd, J=3 Hz, 2 Hz),6.64 (1H, d, J=3 Hz), 7.48 (1H, d, J=15 Hz), 7.49 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 191-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

3.11 g (15 mmol) of 1-aminocyclohexanecarboxylic acid ethyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidmethyl ester hydrochloride and 2.43 g (15 mmol) ofbenzofuran-2-carboxylic acid was used instead of 3-furancarboxylic acidin the process according to Reference Example 15 to obtain 3.80 g (80%)of the title compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.33-1.42 (1H, m), 1.50-1.62(2H, m), 1.65-1.78 (3H, m), 1.94-2.02 (2H, m), 2.19-227 (2H, m), 4.21(2H, q, J=7 Hz), 6.75 (1H, br-s), 7.30 (1H, td, J=8 Hz, 1 Hz), 7.43 (1H,td, J=8 Hz, 1 Hz), 7.45 (1H, d, J=1 Hz), 7.53 (1H, dd, J=8 Hz, 1 Hz),7.67 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 201-[(2-Benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid

3.80 g (12 mmol) of1-[(2-benzofuranylcarbonyl)amino]cyclohexanecarboxylic acid ethyl esterwas used instead of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference Example 16 toobtain 3.42 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.44 (1H, m), 1.50-1.62 (2H, m), 1.65-1.73 (1H,m), 1.74-1.82 (2H, m), 2.00-2.08 (2H, m), 2.25-2.33 (2H, m), 6.77 (1H,br-s), 7.32 (1H, td, J=8 Hz, 1 Hz), 7.46 (1H, td, J=8 Hz, 1 Hz), 7.53(1H, d, J=1 Hz), 7.55 (1H, dd, J=8 Hz, 1 Hz), 7.70 (1H, dd, J=8 Hz, 1Hz)

REFERENCE EXAMPLE 21 1-[(Cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

3.85 g (30 mmol) of cyclohexanecarboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference Example7 to obtain 4.77 g (46%) of the title compound.

1H-NMR (CDCl₃, δ): 1.17-1.45 (8H, m), 1.59-1.77 (4H, m), 1.73-1.88 (6H,m), 2.03-2.11 (3H, m), 5.12 (2H, s), 5.55 (1H, br-s), 7.23-7.36 (5H, m)

REFERENCE EXAMPLE 22 1-[(Cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid

5.62 g (16.3 mmol) of 1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 4.15 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.18-1.50 (8H, m), 1.60-1.76 (4H, m), 1.78-1.95 (6H,m), 2.06-2.14 (2H, m), 2.16-2.23 (1H, m), 5.58 (1H, br-s)

REFERENCE EXAMPLE 231-[(6-Benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester

1.15 g (6.4 mmol) of benzothiazole-6-carboxylic acid was used instead of4-biphenylcarboxylic acid in the process according to Reference Example7 to obtain 1.58 g (62%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.43 (1H, m), 1.49-1.60 (2H, m), 1.61-1.78 (3H,m), 1.96-2.06 (2H, m), 2.20-2.27 (2H, m), 5.19 (2H, s), 6.30 (1H, br-s),7.28-7.75 (5H, m), 7.86 (1H, dd, J=7 Hz, 2 Hz), 8.17 (1H, dd, J=7 Hz, 1Hz), 8.41 (1H, dd, J=2 Hz, 1 Hz), 9.12 (1H, s)

REFERENCE EXAMPLE 241-[(6-Benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid

1.18 g (30 mmol) of1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 0.77 g (84%) ofthe title compound.

1H-NMR (CD₃OD, δ): 1.38-1.46 (1H, m), 1.60-1.76 (5H, m), 1.91-2.01 (2H,m), 2.21-2.28 (2H, m), 7.98 (1H, dd, J=7 Hz, 2 Hz), 8.12 (1H, dd, J=7Hz, 1 Hz), 8.54 (1H, dd, J=2 Hz, 1 Hz), 9.37 (1H, s)

REFERENCE EXAMPLE 251-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

139 mg (1.0 mmol) of 6-hydroxy-3-pyridinecarboxylic acid was usedinstead of 4-biphenylcarboxylic acid in the process according toReference Example 7 to obtain 222 mg (62%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.40 (1H, m), 1.42-1.54 (2H, m), 1.62-1.73 (3H,m), 1.91-1.98 (2H, m), 2.13-2.20 (2H, m), 5.17 (2H, s), 6.22 (1H, s),6.54 (1H, d, J=10 Hz), 7.26-7.35 (5H, m), 7.76° (1H, dd, J=10 Hz, 3 Hz),7.93 (1H, d, J=3 Hz)

REFERENCE EXAMPLE 261-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

760 mg (2.2 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 565 mg(quantitative) of the title compound.

1H-NMR (CD₃OD, 5): 1.21-1.30 (1H, m), 1.43-1.54 (5H, m), 1.67-1.74 (2H,m), 2.03-2.09 (2H, m), 6.33 (1H, d, J=9 Hz), 7.84 (1H, dd, J=9 Hz, 3Hz), 8.05 (1H, d, J=3 Hz)

REFERENCE EXAMPLE 27 1-[(2-Thienylcarbonyl)amino]cyclohexanecarboxylicacid

100 g (680 mmol) of 2-thiophenecarbonyl chloride was used instead of2-furancarbonyl chloride in the process according to Reference Example14 to obtain 57.6 g (51%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.54 (3H, m), 1.65-1.80 (3H, m), 1.98-2.05 (2H,m), 2.21-2.27 (2H, m), 6.06 (1H, br-s), 7.13 (1H, dd, J=5 Hz, 3 Hz),7.57 (1H, dd, J=5 Hz, 1 Hz), 7.59 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 28 1-[(2-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 600 mg (76%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.42 (1H, m), 1.51-1.73 (5H, m), 1.95 (2H, td,J=13 Hz, 4 Hz), 1.99-2.08 (2H, m), 3.73 (3H, s), 7.44 (1H, ddd, J=8 Hz,5 Hz, 2 Hz), 7.84 (1H, dd, J=8 Hz, 2 Hz), 8.16 (1H, d, J=8 Hz), 8.33(1H, s), 8.57 (1H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 29 1-[(2-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

539 mg (2 mmol) of 1-[(2-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 479 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.48-1.57 (2H, m), 1.62-1.78 (3H,m), 1.98 (2H, m), 2.25-2.35 (2H, m), 7.50 (1H, ddd, J=8 Hz, 5 Hz, 2 Hz),7.89 (1H, dd, J=8 Hz, 2 Hz), 8.19 (1H, d, J=8 Hz), 8.59 (1H, s), 8.60(1H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 30 1-[(3-Thienylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

384 mg (3 mmol) of 3-thiophenecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 759 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.42-1.55 (2H, m), 1.61-1.75 (3H,m), 1.90-1.99 (2H, m), 2.11-2.18 (2H, m), 3.74 (3H, s), 6.26 (1H, br-s),7.35 (1H, dd, J=5 Hz, 2 Hz), 7.39 (1H, dd, J=5 Hz, 2 Hz), 7.88 (1H, dd,J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 31 1-[(3-Thienylcarbonyl)amino]cyclohexanecarboxylicacid

759 mg (2.8 mmol) of 1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 692 mg (96%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.24-1.32 (1H, m), 1.45-1.55 (5H, m), 1.72-1.78(2H, m), 2.05-2.12 (2H, m), 7.50 (1H, dd, J=5 Hz, 2 Hz), 7.57 (1H, dd,J=5 Hz, 2 Hz), 7.96 (1H, br-s), 8.21 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 321-[[(3-Ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 581 mg (3 mmol) of1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 482 mg(3.1 mmol) of 1-hydroxybenzotriazole, 517 mg (3 mmol) of3-ethoxy-2-thiophenecarboxylic acid and 1.16 g (9 mmol) ofdiisopropylethylamine in 10 ml of methylene chloride under ice-cooling.After the mixture was stirred at room temperature overnight, thereaction solution was concentrated under reduced pressure, ethyl acetatewas added thereto, and the mixture was washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution, and then saturated brine, followed by dryingwith anhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diisopropyl ether was added to the residue, themixture was stirred overnight, and the crystal was collected byfiltration. Then, the obtained crystal was dissolved in 3 ml oftetrahydrofuran solution, and 2.8 ml of 2N—NaOH aqueous solution wasadded thereto, followed by heating under reflux for 3 hours. Ether wasadded to the reaction solution, and the aqueous layer was separated.After the separated aqueous layer was neutralized by concentratedhydrochloric acid, it was extracted with ethyl acetate. After theobtained organic layer was washed with saturated brine, it was driedwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 656 mg (73%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.40 (1H, m), 1.43-1.54 (2H, m), 1.50 (3H, t,J=7 Hz), 1.62-1.76 (3H, m), 1.90-2.00 (2H, m), 2.22-2.30 (2H, m), 4.30(2H, q, J=7 Hz), 6.87 (1H, d, J=6 Hz), 7.49 (1H, d, J=6 Hz), 7.60 (1H,s)

REFERENCE EXAMPLE 331-[[(S)-1-Oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid methylester

451 mg (3 mmol) of (S)-(+)-2-phenylpropionic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 601 mg (69%) of the title compound.

1H-NMR (CDCl₃, δ): 1.06-1.22 (2H, m), 1.48-1.61 (7H, m), 1.71-1.77 (2H,m), 1.90-1.96 (2H, m), 3.60 (1H, q, 7 Hz), 3.67 (3H, s), 5.40 (1H,br-s), 7.27-7.39 (5H, m)

REFERENCE EXAMPLE 341-[[(S)-1-Oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid

608 mg (2.1 mmol) of1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 366 mg (63%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.08-1.21 (2H, m), 1.28-1.47 (7H, m), 1.53-1.62(2H, m), 1.93 (2H, br-s), 3.79 (1H, q, J=7 Hz), 7.18-7.21 (1H, m),7.27-7.33 (4H, m), 7.90 (1H, s), 12.00 (1H, s)

REFERENCE EXAMPLE 35 1-[(2-Pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

372 mg (3 mmol) of 2-pyrazinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 476 mg (60%) of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.40 (1H, m), 1.47-1.59 (2H, m), 1.65-1.75 (3H,m), 1.94-2.00 (2H, m), 2.18-2.29 (2H, m), 3.75 (3H, s), 8.03 (1H, s),8.55 (1H, dd, J=3 Hz, 1 Hz), 8.77 (1H, d, J=3 Hz), 9.38 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 36 1-[(2-Pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid

476 mg (1.8 mmol) of 1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 356 mg (79%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.28-1.59 (6H, m), 1.79 (2H, td, J=12 Hz, 4 Hz),2.10-2.19 (2H, m), 8.35 (1H, s), 8.75 (1H, d, J=2 Hz), 8.89 (1H, d, J=2Hz), 9.14 (1H, d, J=2 Hz), 12.42 (1H, s)

REFERENCE EXAMPLE 371-[[(5-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

427 mg (3 mmol) of 5-methyl-2-thiophenecarboxylic acid was used insteadof 3-furancarboxylic acid in the process according to Reference Example15 to obtain 812 mg (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.72 (6H, m), 1.92 (2H, td, J=13 Hz, 4 Hz),2.11-2.19 (2H, m), 2.51 (3H, s), 3.73 (3H, s), 5.95 (1H, s), 6.74 (1H,d, J=4 Hz), 7.34 (1H, d, J=4 Hz)

REFERENCE EXAMPLE 381-[[(5-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

812 mg (2.9 mmol) of1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 771 mg (99%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.21-1.38 (1H, m), 1.52 (5H, br-s), 1.68-1.80 (2H,m), 2.01-2.12 (2H, m), 2.46 (3H, s), 6.84 (1H, d, J=4 Hz), 7.70 (1H, s),8.02 (1H, s)

REFERENCE EXAMPLE 391-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 512 mg (3 mmol) of 4-methoxybenzoyl chloride wasused instead of phenylacetyl chloride in the process according toReference Example 1 to obtain 619 mg (71%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.41 (1H, m), 1.49-1.74 (5H, m), 1.94 (2H, td,J=13 Hz, 4 Hz), 2.12-2.22 (2H, m), 3.73 (3H, s), 3.85 (3H, s), 6.16 (1H,br-s), 6.92 (2H, dd, J=7 Hz, 2 Hz), 7.76 (2H, dd, J=7 Hz, 2 Hz)

REFERENCE EXAMPLE 401-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid

619 mg (2.1 mmol) of1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 552 mg (94%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.38 (1H, m), 1.51-1.60 (5H, br-s), 1.65-1.79(2H, m), 2.04-2.19 (2H, m), 3.81 (3H, s), 6.98 (2H, d, J=9 Hz), 7.83(2H, d, J=9 Hz), 8.04 (1H, s), 12.3 (1H, br-s)

REFERENCE EXAMPLE 411-[[(3-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester

581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 482 mg (3 mmol) of 3-methyl-2-thiophenecarbonylchloride was used instead of phenylacetyl chloride in the processaccording to Reference Example 1 to obtain 394 mg (47%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.49-1.53 (2H, m), 1.70-1.72 (3H,m), 1.92 (2H, td, J=12 Hz, 4 Hz), 2.11-2.22 (2H, m), 2.36 (3H, s), 3.74(3H, s), 6.33 (1H, d, J=2 Hz), 6.44 (1H, br-s), 7.30 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 421-[[(3-Methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid

394 mg (1.4 mmol) of1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 330 mg (88%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.36-1.53 (3H, m), 1.68-1.78 (3H, m), 1.96-2.05 (2H,m), 1.99-2.08 (2H, m), 2.55 (3H, s), 5.91 (1H, s), 6.94 (1H, d, J=5 Hz),7.35 (1H, d J=5 Hz)

REFERENCE EXAMPLE 431-[[(3-Methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid

756 mg (6 mmol) of 3-methyl-2-furancarboxylic acid was used instead of3-ethoxy-2-thiophenecarboxylic acid in the process according toReference Example 32 to obtain 902 mg (59%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.20-1.38 (1H, m), 1.40-1.59 (5H, m), 1.70-1.80(2H, m), 2.02-2.18 (2H, m), 2.25 (3H, s), 6.50 (1H, d, J=1 Hz), 7.67(1H, s), 7.68 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 44 1-[(3-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of 3-pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 539 mg (68%) of the title compound;

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.45-1.55 (2H, m), 1.62-1.78 (3H,m), 1.92-2.01 (2H, m), 2.12-2.21 (2H, m), 3.75 (3H, s), 6.27 (1H, s),7.40 (1H, dd, J=8 Hz, 5 Hz), 8.12 (1H, d, J=8 Hz), 8.74 (1H, d, J=5 Hz),9.00 (1H, s)

REFERENCE EXAMPLE 45 1-[(3-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

539 mg (2 mmol) of 1-[(3-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 508 mg(quantitative) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.35 (1H, m), 1.49-1.62 (5H, m), 1.69-1.82(2H, m), 2.09-2.17 (2H, m), 7.50 (1H, dd, J=8 Hz, 5 Hz), 8.16 (1H, d,J=8 Hz), 8.44 (1H, s), 8.71 (1H, d, J=5 Hz), 8.97 (1H, s), 12.24 (1H,br-s)

REFERENCE EXAMPLE 461-[[(1-Methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

375 mg (3 mmol) of 1-methyl-2-pyrrolecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 320 mg (40%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.40 (1H, m), 1.44-1.55 (2H, m), 1.61-1.74 (3H,m), 1.86-1.95 (2H, m), 2.05-2.16 (2H, m), 3.73 (3H, s), 3.89 (3H, s),5.97 (1H, s), 6.09 (1H, dd, J=4 Hz, 3 Hz), 6.59 (1H, dd, J=4 Hz, 2 Hz),6.71 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 471-[[(1-Methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid

320 mg (1.2 mmol) of1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 187 mg (62%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.31-1.53 (3H, m), 1.62-1.79 (3H, m), 1.91-2.02 (2H,m), 2.18-2.24 (2H, m), 3.93 (3H, s), 5.92 (1H, s), 6.14 (1H, dd, J=4 Hz,3 Hz), 6.68 (1H, dd, J=4 Hz, 2 Hz), 6.81 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 481-[((R)-1-Oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid methylester

451 mg (3 mmol) of (R)-(−)-2-phenylpropionic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 435 mg (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.03-1.22 (3H, m), 1.48-1.62 (6H, m), 1.88-2.00 (2H,m), 3.60 (3H, q, J=7 Hz), 3.68 (3H, s), 5.40 (1H, br-s), 7.27-7.39 (5H,m)

REFERENCE EXAMPLE 491-[((R)-1-Oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid

435 mg (1.5 mmol) of1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 349 mg (84%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.15-1.23 (2H, m), 1.29 (3H, d, J=7 Hz) 1.35-1.53(4H, m), 1.53-1.63 (2H, m), 1.91 (2H, br-s), 3.78 (1H, q, J=7 Hz),7.18-7.20 (1H, m), 7.21-7.32 (4H, m), 7.90 (1H, s), 12.00 (1H, s)

REFERENCE EXAMPLE 501-[(1H-Indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

483 mg (3 mmol) of indole-5-carboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 766 mg (85%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.16-1.33 (1H, m), 1.54-1.63 (5H, m), 1.75-1.80(2H, m), 2.04-2.18 (2H, m), 3.33 (3H, s), 6.52-6.56 (1H, m), 7.40 (1H,s), 7.41-7.44 (1H, m), 7.60 (1H, dd, J=9 Hz, 2 Hz), 8.14 (1H, d, J=2Hz), 8.18 (1H, s), 11.32 (1H, s)

REFERENCE EXAMPLE 511-[(1H-Indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid

766 mg (2.6 mmol) of1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl esterwas used instead of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference Example 16 toobtain 561 mg (77%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.38 (1H, m), 1.55-1.62 (5H, m), 1.63-1.79(2H, m), 2.10-2.22 (2H, m), 6.54 (1H, d, J=3 Hz), 7.40-7.43 (2H, m),7.60 (1H, dd, J=3 Hz, 1 Hz), 8.03 (1H, s), 8.14 (1H, s), 11.31 (1H, s),12.04 (1H, s)

REFERENCE EXAMPLE 521-[(1-Cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid methylester

336 mg (3 mmol) of 1-cyclopentenecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 717 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.44 (2H, m), 1.60-1.70 (4H, m), 1.87 (2H, td,J=9 Hz, 4 Hz)., 1.99-2.09 (4H, m), 2.49 (2H, m), 2.58 (2H, m), 3.72 (3H,s), 5.75 (1H, br-s), 6.55 (1H, t, J=2 Hz)

REFERENCE EXAMPLE 531-[(1-Cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid

717 mg (2.9 mmol) of1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 588 mg (87%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.24 (1H, d, J=8 Hz), 1.40-1.50 (5H, m), 1.67 (2H,td, J=10 Hz, 9 Hz), 1.81-1.89 (2H, m), 1.91-2.09 (2H, m), 2.40-2.50 (4H,m), 6.53 (1H, t, J=3 Hz), 7.46 (1H, s), 12.03 (1H, s)

REFERENCE EXAMPLE 54 1-[(4-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester

370 mg (3 mmol) of 4-pyridinecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 609 mg (77%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.53 (3H, m), 1.62-1.77 (3H, m), 1.92-2.03 (2H,m), 2.13-2.21 (2H, m), 3.75 (3H, s), 6.29 (1H, br-s), 7.62 (2H, dd, J=5Hz, 2 Hz), 8.76 (2H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 55 1-[(4-Pyridinylcarbonyl)amino]cyclohexanecarboxylicacid

609 mg (2.3 mmol) of 1-[(4-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino)cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 522 mg (97%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.22-1.33 (1H, m), 1.46-1.59 (5H, m), 1.70-1.80(2H, m), 2.09-2.15 (2H, m), 7.73 (2H, dd, J=5 Hz, 2 Hz), 8.51 (1H, s),8.72 (2H, dd, J=5 Hz, 2 Hz)

REFERENCE EXAMPLE 561-[(1H-Pyrrol-2-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

278 mg (2.5 mmol) of 2-pyrrolecarboxylic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 534 mg (85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.45 (2H, m), 1.45-1.53 (2H, m), 1.62-1.72 (2H,m), 1.93 (2H td, J=13 Hz, 4 Hz), 2.08-2.19 (2H, m), 3.70 (3H, s), 6.05(1H, br-s), 6.23-6.25 (1H, m), 6.61 (1H, d, J=2 Hz), 6.94 (1H, d, J=2Hz)

REFERENCE EXAMPLE 571-[(1H-Pyrrol-2-ylcarbonyl)amino]cyclohexanecarboxylic acid

500 mg (2 mmol) of1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 338 mg (71%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.20-1.31 (1H, m), 1.52 (5H, br-s), 1.70-1.80 (2H,m), 2.04-2.18 (2H, m), 6.08 (1H, dd, J=4 Hz, 2 Hz), 6.85-6.89 (2H, m),7.59 (1H, s), 11.39 (1H, s), 12.09 (1H, br-s)

REFERENCE EXAMPLE 581-[[(6-Hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 6-hydroxy-pyridinecarboxylic acid was used insteadof 3-furancarboxylic acid in the process according to Reference Example15 to obtain 1.32 g (47%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (1H, m), 1.65 (5H, m), 1.96 (2H, td, J=12Hz, 4 Hz), 2.10-2.21 (2H, m), 3.73 (3H, s), 6.71 (1H, d, J=9 Hz), 7.20(1H, d, J=7 Hz), 7.62 (1H, dd, J=9 Hz, 7 Hz), 8.00 (1H, s)

REFERENCE EXAMPLE 591-[[(6-Hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

1.32 mg (4.7 mmol) of1-[[(6-hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 1.16 g (88%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.39-1.50 (1H, m), 1.39-1.50 (2H, m), 1.51-1.63(3H, m), 1.70-1.82 (2H, m), 2.01-2.12 (2H, d, m), 6.78 (1H, d, J=8 Hz),7.32 (1H, br-s), 7.74 (1H, t, J=8 Hz), 8.18 (1H, s)

REFERENCE EXAMPLE 601-[[(2-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 2-hydroxynicotinic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 697 mg (25%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.38 (1H, m), 1.50-1.62 (2H, m), 1.64-1.74 (3H,m), 1.82-1.93 (2H, m), 2.15-2.24 (2H, m), 3.74 (3H, s), 6.53 (1H, t, J=7Hz), 7.49 (1H, d, J=7 Hz), 8.57 (1H, d, J=7 Hz), 10.04 (1H, s)

REFERENCE EXAMPLE 611-[[(2-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid

698 mg (2.5 mmol) of1-[[(2-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 580 mg (83%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.21-1.31 (1H, m), 1.38-1.41 (2H, m), 1.59 (3H, d,J=10 Hz), 1.67-1.72 (2H, m), 1.98-2.04 (2H, m), 6.49 (1H, t, J=7 Hz),7.73 (1H, br-s), 8.28 (1H, d, J=7 Hz), 10.21 (1H, s), 12.19 (1H, s),12.53 (1H, br-s)

REFERENCE EXAMPLE 621-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

1.39 g (10 mmol) of 6-hydroxynicotinic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 869 mg (31%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (1H, m), 1.43-1.58 (2H, m), 1.61-1.75 (3H,m), 1.89-1.99 (2H, m), 2.11-2.19 (2H, m), 3.74 (3H, s), 6.43 (1H, s),6.53 (1H, d, J=10 Hz), 7.82 (1H, dd, J=10 Hz, 2 Hz), 8.05 (1H, d, J=2Hz)

REFERENCE EXAMPLE 631-[[(6-Hydroxy-3-pyridinyl)carbonyl]amino)cyclohexanecarboxylic acid

869 mg (3.1 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 818 mg (94%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.19-1.31 (1H, m), 1.42-1.57 (5H, m), 1.67-1.78(2H, m), 2.01-2.11 (2H, m), 6.34 (1H, d, J=10 Hz), 7.84 (1H, dd, J=10Hz, 2 Hz), 7.95 (1H, s), 8.05 (1H, d, J=2 Hz), 11.90-12.18 (2H, m)

REFERENCE EXAMPLE 641-[[1-oxo-3-(2-furanyl)propyl]amino]cyclohexanecarboxylic acid methylester

420 mg (3 mmol) of 3-(2-furyl)propionic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 478 mg (57%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.38 (3H, m), 1.57-1.65 (3H, m), 1.78-1.85 (2H,m), 1.96-2.01 (2H, m), 2.56 (2H, t, J=7 Hz), 2.98 (2H, t, J=7 Hz), 3.69(3H, s), 5.56 (1H, br-s), 6.06 (1H, dd, J=3 Hz, 2 Hz), 6.29 (1H, dd, J=3Hz, 2 Hz), 7.31 (1H, dd, J=3 Hz, 2 Hz)

REFERENCE EXAMPLE 651-[[[1-(2-Propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

646 mg (3 mmol) of 1-(2-propoxycarbonyl)nipecotinic acid was usedinstead of 3-furancarboxylic acid in the process according to ReferenceExample 15 to obtain 979 mg (92%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24 (6H, d, J=6 Hz), 1.25-1.44 (3H, m) 1.56-1.70(5H, m), 1.79-1.90 (4H, m), 1.98-2.07 (2H, m), 2.26-2.34 (1H, m),2.75-2.88 (2H, m), 3.69 (3H, s), 4.17 (2H, br-s), 4.86-4.96 (1H, m),5.58 (1H, s)

REFERENCE EXAMPLE 661-[[[1-(2-Propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

979 mg (2.76 mmol) of1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 940 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.28 (7H, m), 1.34-1.39 (3H, m), 1.62-1.71 (6H,m), 1.85-1.91 (4H, m), 2.05-2.09 (2H, m), 2.33-2.36 (1H, m), 2.74-2.84(2H, m), 4.21 (1H, br-s), 4.91 (1H, q, J=7 Hz), 5.67 (1H, s)

REFERENCE EXAMPLE 671-[[[1-(Ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

604 mg (3 mmol) of 1-ethoxycarbonylnipecotinic acid was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 976 mg (95%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.25-1.42 (3H, m), 1.55-1.70(3H, m), 1.81-1.86 (4H, m), 2.01-2.05 (3H, m), 2.26-2.32 (1H, m),2.80-2.89 (2H, m), 3.69 (3H, s), 4.08-4.23 (3H, m), 4.13 (2H, q, J=7Hz), 5.54 (1H, br-s)

REFERENCE EXAMPLE 681-[[[1-(Ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

976 mg (2.87 mmol) of1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 935 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.42 (3H, m), 1.62-1.72(5H, m), 1.85-1.91 (4H, m), 2.06-2.09 (2H, m), 2.34-2.39 (1H, m),2.79-2.90 (2H, m), 4.10-4.25 (3H., m), 4.13 (2H, q, J=7 Hz), 5.69 (1H,s)

REFERENCE EXAMPLE 691-[[[1-(2-Furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

670 mg (3 mmol) of 1-(2-furanylcarbonyl)piperidine-4-carboxylic acid wasused instead of 3-furancarboxylic acid in the process according toReference Example 15 to obtain 910 mg (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.43 (3H, m), 1.53-1.69 (3H, m), 1.74-1.90 (4H,m), 1.91-2.05 (4H, m), 2.43-2.48 (1H, m), 2.89-3.21 (2H, m), 3.79 (3H,s), 4.40-4.56 (2H, m), 5.58 (1H, br-s), 6.47 (1H, dd, J=3 Hz, 1 Hz),6.95 (1H, dd, J=3 Hz, 1 Hz), 7.48 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 701-[[[1-(2-Furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid

910 mg (2.4 mmol) of1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 196 mg (23%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.17-1.25 (1H, m), 1.40-1.58 (7H, m), 1.58-1.62(2H, m), 1.73-1.76 (2H, m), 1.93-1.96 (2H, m), 2.51-2.61 (1H, m),2.80-3.11 (2H, m), 4.22-4.33 (2H, m), 6.61 (1H, dd, J=3 Hz, 1 Hz), 6.95(1H, dd, J=3 Hz, 1 Hz), 7.78 (1H, s), 7.82 (1H, dd, J=3 Hz, 1 Hz)

REFERENCE EXAMPLE 711-[[[(2-Furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidmethyl ester

507 mg (3 mmol) of N-(2-furanylcarbonyl)glycine was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 781 mg (88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.38 (1H, m), 1.39-1.50 (2H, m), 1.58-1.69 (3H,m), 1.85 (2H, td, J=9 Hz, 4 Hz), 2.02-2.10 (2H, m), 3.70 (3H, s), 4.15(2H, d, J=6 Hz), 6.51 (1H, dd, J=2 Hz, 1 Hz), 6.67 (1H, s), 7.13 (2H,m), 7.47 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 721-[[[(2-Furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acid

781 mg (2.7 mmol) of1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidmethyl ester was used instead of1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester inthe process according to Reference Example 16 to obtain 320 mg (41%) ofthe title compound.

1H-NMR (DMSO-d₆, δ): 1.12-1.25 (1H, m), 1.39-1.58 (5H, m), 1.64 (2H, td,J=13 Hz, 4 Hz), 1.90-2.02 (2H, m), 3.88 (2H, d, J=6 Hz), 6.62 (1H, dd,J=3 Hz, 1 Hz), 7.13 (1H, dd, J=3 Hz, 1 Hz), 7.84 (1H, d, J=1 Hz), 7.87(1H, s), 8.38 (1H, d, J=6 Hz)

REFERENCE EXAMPLE 731-[[(Benzoylamino)acetyl]amino]cyclohexanecarboxylic acid methyl ester

538 mg (3 mmol) of N-benzoylglycine was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 812 mg (81%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.48 (2H, td, J=9 Hz, 4 Hz),1.58-1.71 (3H, m), 1.84 (2H, dt, J=9 Hz, 4 Hz), 2.02-2.10 (2H, m), 3.70(3H, s), 4.21 (2H, d, J=7 Hz), 7.08 (1H, br-s), 7.26-7.46 (3H, m), 7.54(1H, td, J=8 Hz, 1 Hz), 7.84 (2H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 741-[[(Benzoylamino)acetyl]amino]cyclohexanecarboxylic acid

812 mg (2.4 mmol) of1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid methyl esterwas used instead of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference Example 16 toobtain 724 mg (93%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.09-1.67 (8H, m), 1.96 (2H, d, J=11 Hz) 3.93 (2H,d, J=6 Hz), 7.47 (2H, td, J=6 Hz, 1 Hz), 7.52-7.55 (1H, m), 7.86-7.89(3H, m), 8.64 (1H, t, J=6 Hz)

REFERENCE EXAMPLE 751-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methylester

3.67 g (30 mmol) of dimethylaminopyridine was added to a solution of65.48 g (0.3 mol) of di-t-butyl dicarbonate in 300 ml of anhydroustoluene, and the mixture was stirred at room temperature for 15 minutes.A solution of 47.17 g (0.3 mol) of 1-aminocyclohexanecarboxylic acidmethyl ester in 100 ml of anhydrous toluene was added to the reactionsolution, and the mixture was stirred at room temperature for 1 hour.Further, after 60.71 g (0.6 mol) of triethylamine and 44.1 g (0.45 mol)of furfuryl alcohol were added, the mixture was heated under reflux for3 hours. The reaction solution was returned to room temperature andconcentrated under reduced pressure. The obtained residue was crushed ina mortar and stirred in a mixture solution of 5 ml of hydrochloric acidand 3 L of water for 18 hours. The obtained crystal was collected byfiltration to obtain 74.37 g (88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.36 (1H, m), 1.38-1.51 (2H, m), 1.55-1.65 (3H,m), 1.80-1.88 (2H, m), 1.93-2.04 (2H, m), 3.71 (3H, br-s), 4.93 (1H,br-s), 5.04 (2H, s), 6.36 (1H, dd, J=3 Hz, 2 Hz), 6.41 (1H, d, J=3 Hz),7.43 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 761-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid

28.13 g (0.1 mol) of1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid methylester was added to a mixture solution of 150 ml of 2N aqueous sodiumhydroxide solution and 200 ml of tetrahydrofuran, and the mixture washeated under reflux for 18 hours. After the solvent was distilled off,water was added to the residue and the mixture was washed with diethylether.

After potassium hydrogensulfate was added to the aqueous layer toacidify it, the mixture was extracted with ethyl acetate twice. Afterthe organic layer was washed with saturated brine, it was dried withanhydrous magnesium sulfate, and thereafter the solvent was distilledoff under reduced pressure. Diisopropyl ether was added to the residue,and the mixture was stirred for 18 hours. The obtained crystal wascollected by filtration to obtain 19.89 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.37 (1H, m), 1.38-1.52 (2H, m), 1.59-1.71 (3H,m), 1.82-1.93 (2H, m), 1.99-2.12 (2H, m), 4.99 (1H, br-s), 5.07 (2H, s),6.37 (1H, dd, J=3 Hz, 2 Hz), 6.42 (1H, d, J=3 Hz), 7.43 (1H, d, J=2 Hz)

REFERENCE EXAMPLE 771-[[(4-Phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 366 mg (3 mmol) of N,N-dimethylaminopyridine and 6.99 g(30 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inmethylene chloride was added to a solution of 6.55 g (30 mmol) ofdi-t-butyl dicarbonate in 150 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 6.07 g (60 mmol) of triethylamine and 5.11 g (33 mmol) of1-phenylpiperazine in methylene chloride was added, and the mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the obtained crystal was washed with diethyl ether toobtain 8.88 g (70%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.37 (1H, m), 1.42-1.51 (2H, m), 1.50-1.69 (3H,m), 1.82-1.91 (2H, m), 2.03-2.10 (2H, m), 3.17 (4H, t, J=5 Hz), 3.54(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.89-6.94 (3H, m),7.26-7.35 (7H, m)

REFERENCE EXAMPLE 781-[[(4-Phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid

8.88 g (21 mmol) of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester obtained in Reference Example 77 was dissolved in 200ml of methanol, 900 mg of 10% palladium-carbon was added thereto, andthe mixture was stirred under a hydrogen atmosphere at room temperatureovernight. After the reaction solution was filtered, the filtrate wasconcentrated under reduced pressure to obtain 6.96 g (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.22-1.30 (1H, m), 1.36-1.42 (2H, m), 1.50-2.05 (5H,m), 2.06-2.14 (2H, m), 3.24 (4H, t, J=5 Hz), 4.61 (4H, t, J=5 Hz), 4.51(1H, br-s), 6.92-6.95 (2H, m), 7.28-7.32 (3H, m)

REFERENCE EXAMPLE 791-[[[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

3.43 g (21 mmol) of 1-(2-pyridinyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 7.33 g (87%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26-1.35 (1H, m), 1.42-1.53 (2H, m), 1.60-1.68 (3H,m), 1.83-1.92 (2H, m), 2.02-2.10 (2H, m), 3.52 (4H, t, J=5 Hz), 3.57(4H, t, J=5 Hz), 4.58 (1H, br-s), 5.15 (2H, s), 6.63 (1H, d, J=8 Hz),6.67 (1H, td, J=8 Hz, 1 Hz), 7.25-7.34 (5H, m), 7.51 (1H, td, J=8 Hz, 1Hz), 8.20 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 801-[[[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

7.33 g (17.4 mmol) of1-[[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 5.75 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.43 (2H, m), 1.60-1.72 (4H, m), 1.89-1.99 (2H,m), 2.06-2.13 (2H, m), 3.61 (4H, t, J=5 Hz), 3.66 (4H, t, J=5 Hz), 4.61(1H, br-s), 6.65 (1H, dd, J=8 Hz, 1 Hz), 6.69 (1H, td, J=8 Hz, 1 Hz),7.52 (1H, td, J=8 Hz, 1 Hz), 8.20 (1H, dd, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 811-[[[4-(4-Fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

3.78 g (21 mmol) of 1-(4-fluorophenyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 4.48 g (51%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.35 (1H, m), 1.40-1.51 (2H, m), 1.55-1.70 (3H,m), 1.85-1.93 (2H, m), 2.02-2.09 (2H, m), 3.07 (4H, t, J=5 Hz), 3.53(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 6.87 (2H, ddd, J=9 Hz, 6Hz, 2 Hz), 6.98 (2H, ddd, J=9 Hz, 6 Hz, 2 Hz), 7.25-7.35 (5H, m)

REFERENCE EXAMPLE 821-[[[4-(4-Fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

4.48 g (10 mmol) of1-[[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 3.56 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.43 (3H, m), 1.60-1.75 (3H, m), 1.89-2.01 (2H,m), 2.05-2.13 (2H, m), 3.14 (4H, t, J=5 Hz), 3.61 (4H, t, J=5 Hz), 4.55(1H, br-s), 6.89 (2H, ddd, J=8 Hz, 5 Hz, 2 Hz), 6.99 (2H, ddd, J=8 Hz, 5Hz, 2 Hz)

REFERENCE EXAMPLE 831-[[[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

4.83 g (21 mmol) of 1-[3-(trifluoromethyl)phenyl]piperazine was usedinstead of 1-phenylpiperazine in the process according to ReferenceExample 77 to obtain 7.54 g (77%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.37 (1H, m), 1.42-1.53 (2H, m), 1.59-1.70 (3H,m), 1.85-1.94 (2H, m), 2.02-2.10 (2H, m), 3.21 (4H, t, J=5 Hz), 3.55(4H, t, J=5 Hz), 4.60 (1H, br-s), 5.15 (2H, s), 7.05 (1H, dd, J=8 Hz, 2Hz), 7.09 (1H, s), 7.12 (1H, dd, J=8 Hz, 2 Hz), 7.25-7.40 (6H, m)

REFERENCE EXAMPLE 841-[[[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

7.54 g (15.4 mmol) of1-[[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 5.92 g (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.44 (2H, m), 1.60-1.75 (4H, m), 1.91-2.00 (2H,m), 2.05-2.14 (2H, m), 3.30 (4H, t, J=5 Hz), 3.63 (4H, t, J=5 Hz), 4.63(1H, br-s), 7.07 (1H, d, J=8 Hz), 7.11 (1H, s), 7.15 (1H, d, J=8 Hz),7.38 (1H, t, J=8 Hz)

REFERENCE EXAMPLE 851-[[(4-Cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.66 g (15.8 mmol) of 1-(cyclohexyl)piperazine was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 3.21 g (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.45 (3H, m), 1.39-1.50 (3H, m), 1.51-1.67 (6H,m), 1.89-1.90 (6H, m), 2.01-2.07 (2H, m), 2.22-2.30 (1H, m), 2.54 (4H,t, J=5 Hz), 3.38 (4H, t, J=5 Hz), 4.53 (1H, br-s), 5.14 (2H, s),7.25-7.34 (5H, m)

REFERENCE EXAMPLE 861-[[(4-Cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid

3.21 g (7.5 mmol) of1-[[(4-cyclohexyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 2.53 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.05-1.19 (1H, m), 1.10-1.19 (2H, m), 1.20-1.32 (2H,m), 1.58-1.97 (13H, m), 2.03-2.12 (2H, m), 2.35-2.44 (1H, m), 2.67 (4H,t, J=5 Hz), 3.48 (4H, t, J=5 Hz), 4.59 (1H, br-s)

REFERENCE EXAMPLE 871-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g(9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inmethylene chloride was added to a solution of 2.03 g (9.3 mmol) ofdi-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of1-(benzoyl)piperazine in methylene chloride were added thereto, and themixture was stirred at room temperature overnight. After the reactionsolution was concentrated, the residue was dissolved in ethyl acetate,and the mixture was successively washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the obtained crystal was washed with diethyl ether toobtain 3.60 g (86%) of the title compound.

1H-NMR (CDCl₃, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H,m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m), 3.28-3.57 (6H, m), 3.66-3.85(2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48(6H, m)

REFERENCE EXAMPLE 881-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid

3.60 g (8 mmol) of1-[[(4-benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 2.88 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.42 (2H, m), 1.59-1.74 (2H, m), 1.85-2.10 (6H,m), 3.42-3.58 (6H, m), 3.70-3.87 (2H, m), 4.60 (1H, br-s), 7.39-7.47(5H, m)

REFERENCE EXAMPLE 891-[[[4-(Phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester

5.82 g (33 mmol) of 4-(phenylmethyl)piperazine was used instead of1-phenylpiperazine and 5.14 g (30 mmol) of 1-aminocyclohexanecarboxylicacid ethyl ester was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 77 toobtain 7.62 g (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.24-1.39 (1H, m), 1.40-1.49(2H, m), 1.55-1.64 (3H, m), 1.80-1.89 (2H, m), 1.97-2.04 (2H, m), 2.44(4H, t, J=5 Hz), 3.39 (4H, t, J=5 Hz), 3.52 (2H, s), 4.17 (2H, q, J=7Hz), 4.50 (1H, br-s), 7.23-7.30 (1H, m), 7.30-7.37 (4H, m)

REFERENCE EXAMPLE 901-[[[4-(Phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

600 ml of 1N aqueous sodium hydroxide solution was added to a solutionof 7.62 g (20 mmol) of1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in 300 ml of ethanol, and the mixture was heated underreflux for 2 hours. After ether was added to the reaction solution towash it, the aqueous layer was neutralized by concentrated hydrochloricacid and extracted with ethyl acetate. After the obtained organic layerwas washed with saturated brine, it was dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtain2.90 g (42%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.38 (2H, m), 1.60-1.71 (4H, m), 1.88-1.98° (2H,m), 2.01-2.10 (2H, m), 2.49 (4H, t, J=5 Hz), 3.45 (4H, t, J=5 Hz), 3.55(2H, s), 4.43 (1H, br-s), 7.24-7.34 (5H, m)

REFERENCE EXAMPLE 911-[[4-(1-Oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.40 g (11 mmol) of 1-(1-oxo-3-phenylpropyl)piperazine was used insteadof 1-(benzoyl)piperazine in the process according to Reference Example87 to obtain 3.53 g (74%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.39 (1H, m), 1.40-1.49 (2H, m), 1.58-1.67 (3H,m), 1.84-1.93 (2H, m), 2.00-2.07 (2H, m), 2.62 (2H, t, J=6 Hz), 2.98(2H, t, J=6 Hz), 3.25-3.33 (6H, m), 3.59-3.65 (2H, m), 4.52 (1H, br-s),5.14 (2H, br-s), 7.18-7.23 (4H, m), 7.28-7.34 (6H, m)

REFERENCE EXAMPLE 921-[[[4-(1-Oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

3.53 g (7.4 mmol) of1-[[[4-(1-oxo-3-phenylpropyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 2.87 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.53 (3H, m), 1.57-1.70 (3H, m), 1.84-1.97 (2H,m), 2.00-2.08 (2H, m), 2.63 (2H, t, J=6 Hz), 2.98 (2H, m, J=6 Hz),3.33-3.41 (6H, m), 3.67-3.71 (2H, m), 4.78 (1H, br-s), 7.18-7.25 (3H,m), 7.27-7.34 (2H, m)

REFERENCE EXAMPLE 931-[[[4-(Phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

1.23 g (6 mmol) of 1-(phenylacetyl)piperazine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to ReferenceExample 87 to obtain 2.39 g (87%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.36 (1H, m), 1.37-2.06 (2H, m), 1.55-1.66 (3H,m), 1.83-1.92 (2H, m), 1.98-2.03 (2H, m), 3.20 (2H, t, J=5 Hz), 3.31(2H, t, J=5 Hz), 3.41 (2H, t, J=5 Hz), 3.63 (2H, t, J=5 Hz), 3.74 (2H,s), 4.49 (1H, br-s), 5.12 (2H, s), 7.24-7.32 (10H, m)

REFERENCE EXAMPLE 941-[[[4-(Phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid

2.39 g (5.2 mmol) of1-[[[4-(phenylacetyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 1.94 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.39 (3H, m), 1.58-1.70 (3H, m), 1.86-1.96 (2H,m), 1.99-2.07 (2H, m), 3.26 (2H, t, J=5 Hz), 3.38 (2H, t, J=5 Hz), 3.50(2H, t, J=5 Hz), 3.72 (2H, t, J=5 Hz), 3.76 (2H, s), 4.50 (1H, br-s),7.23-7.30 (3H, m), 7.30-7.35 (2H, m)

REFERENCE EXAMPLE 951-[(1-Piperidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

1.34 g (15.8 mmol) of piperidine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to ReferenceExample 87 to obtain 4.59 g (89%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.34 (1H, m), 1.40-1.65 (11H, m), 1.82-1.90 (2H,m), 2.02-2.08 (2H, m), 3.32 (4H, t, J=5 Hz), 4.53 (1H, br-s), 5.14 (2H,s), 7.29-7.35 (5H, m)

REFERENCE EXAMPLE 961-[(1-Piperidinylcarbonyl)amino]cyclohexanecarboxylic acid

4.59 g (12 mmol) of1-[(1-piperidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 3.05 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (4H, m), 1.56-1.70 (8H, m), 1.85-1.96 (2H,m), 2.05-2.13 (2H, m), 3.89 (4H, t, J=5 Hz), 4.51 (1H, br-s)

REFERENCE EXAMPLE 971-[(1-Pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

1.12 g (15.8 mmol) of pyrrolidine was used instead of1-(1-oxo-3-phenylpropyl)piperazine in the process according to ReferenceExample 87 to obtain 3.23 g (65%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.33 (1H, m), 1.42-1.51 (2H, m), 1.51-1.68 (3H,m), 1.82-1.95 (2H, m), 1.89 (4H, t, J=7 Hz), 2.02-2.10 (2H, m), 3.35(4H, t, J=7 Hz), 4.33 (1H, br-s), 5.16 (2H, s), 7.26-7.36 (5H, m)

REFERENCE EXAMPLE 981-[(1-Pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid

3.23 g (9.8 mmol) of1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 2.35 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.42 (3H, m), 1.58-1.72 (3H, m), 1.88-2.00 (6H,m), 2.05-2.14 (2H, m), 3.40 (4H, t, J=6 Hz), 4.34 (1H, br-s)

REFERENCE EXAMPLE 991-[[(2-Oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

A solution of 183 mg (1.5 mmol) of N,N-dimethylaminopyridine and 3.50 g(15 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester intoluene was added to a solution of 3.27 g (15 mmol) of di-t-butyldicarbonate in 60 ml of toluene, and the mixture was stirred at roomtemperature for 30 minutes. Thereafter, 3.04 g (30 mmol) oftriethylamine, 1.83 g (15 mmol) of N,N-dimethylaminopyridine and 1.56 g(15.8 mmol) of 2-piperidone were added to the reaction mixture, and themixture was heated under reflux overnight. Ethyl acetate was added tothe reaction solution, and the mixture was successively washed withwater, a 10% aqueous potassium hydrogensulfate solution, a saturatedaqueous sodium hydrogencarbonate solution and saturated brine, followedby drying with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure and the obtained residue was purified by silicagel chromatography to obtain 4.10 g (76%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-1.30 (1H, m), 1.42-1.53 (2H, m), 1.61-1.69 (3H,m), 1.78-1.90 (6H, m), 2.06-2.15 (2H, m), 2.54 (2H, t, J=6 Hz), 3.73(2H, t, J=6 Hz), 5.16 (2H, s), 7.27-7.35 (5H, m), 9.85 (1H, br-s)

REFERENCE EXAMPLE 1001-[[(2-Oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acid

4.10 g (11.4 mmol) of1-[[1-(2-oxo-1-piperidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 2.95 g (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.24-1.35 (1H, m), 1.45-1.64 (2H, m), 1.50-1.71 (3H,m), 1.82-1.92 (6H, m), 2.12-2.16 (2H, m), 2.58 (2H, t, J=6 Hz), 3.80(2H, t, J=6 Hz), 9.96 (1H, br-s)

REFERENCE EXAMPLE 1011-[(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester

3.00 g (21 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane was used instead of1-(benzoyl)piperazine in the process according to Reference Example 87to obtain 5.70 g (71%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.34 (1H, m), 1.40-1.48 (2H, m), 1.59-1.67 (3H,m), 1.69 (4H, t, J=6 Hz), 1.84-1.93 (2H, m), 2.00-2.08 (2H, m), 3.47(4H, t, J=6 Hz), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s), 7.27-7.36(5H, m)

REFERENCE EXAMPLE 1021-[(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid

5.70 g (14.2 mmol) of1-[(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 4.38 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (3H, m), 1.60-1.77 (3H, m), 1.75 (4H, t,J=6 Hz), 1.88-2.01 (2H, m), 2.05-2.14 (2H, m), 3.54 (4H, t, J=6 Hz),3.99 (4H, s), 4.55 (1H, br-s)

REFERENCE EXAMPLE 1031-[[[(1,3-Dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.46 g (21 mmol) of 2-[(methylamino)methyl]-1,3-dioxolane was usedinstead of 1-(benzoyl)piperazine in the process according to ReferenceExample 87 to obtain 6.05 g (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.22-1.34 (1H, m), 1.39-1.50 (2H, m), 1.59-1.68 (2H,m), 1.68-1.74 (3H, m), 1.82-1.91 (2H, m), 2.00-2.08 (2H, m), 3.44-3.50(4H, m), 3.98 (4H, s), 4.59 (1H, br-s), 5.14 (2H, s), 7.27-7.36 (5H, m)

REFERENCE EXAMPLE 1041-[[[(1,3-Dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid

6.05 g (16 mmol) of1-[[[(1,3-dioxolan-2-ylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 4.45 g (97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (3H, m), 1.60-1.75 (5H, m), 1.88-1.97 (2H,m), 2.04-2.13 (2H, m), 3.48-3.59 (4H, m), 3.99 (4H, s), 4.53 (1H, br-s)

REFERENCE EXAMPLE 1051-[[(1,3-Dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.50 g (21 mmol) of isoindoline was used instead of1-(benzoyl)piperazine in the process according to Reference Example 87to obtain 5.95 g (79%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.45-1.70 (5H, m), 1.89-1.97 (2H,m), 2.07-2.16 (2H, m), 4.48 (1H, br-s), 4.73 (4H, s), 5.17 (2H, s),7.25-7.31 (7H, m), 7.31-7.36 (2H, m)

REFERENCE EXAMPLE 1061-[[(1,3-Dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid

5.95 g (15.8 mmol) of1-[[(1,3-dihydro-2H-isoindol-2-yl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 3.09 g (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.30 (1H, m), 1.35-1.48 (2H, m), 1.59-1.76 (3H,m), 1.96-2.05 (2H, m), 2.10-2.17 (2H, m), 4.40 (1H, br-s), 4.78 (4H,br-s), 7.24-7.35 (4H, m)

REFERENCE EXAMPLE 1071-[[(2-Oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added toa solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acidphenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml ofchloroform, and the mixture was stirred at 60° C. for four days. Thereaction solution was successively washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, and it was dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure and the obtained crystal was washed with diethyl ether toobtain 2.64 g (82%) of the title compound. 1H-NMR (CDCl₃, δ): 1.22-1.31(1H, m), 1.44-1.54 (2H, m), 1.60-1.68 (3H, m), 1.81-1.88 (2H, m),2.08-2.16 (2H, m), 3.48 (2H, t, J=7 Hz), 3.93 (2H, t, J=7 Hz), 4.75 (1H,br-s), 5.17 (2H, s), 7.26-7.36 (5H, m), 8.45 (1H, br-s)

REFERENCE EXAMPLE 1081-[[(2-Oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acid

2.64 g (7.6 mmol) of1-[[(2-oxo-1-imidazolydinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 1.95 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.41-1.70 (5H, m), 1.83-1.92 (2H,m), 2.11-2.20 (2H, m), 3.54 (2H, t, J=8 Hz), 4.01 (2H, t, J=8 Hz), 4.92(1H, br-s), 8.53 (1H, br-s)

REFERENCE EXAMPLE 1091-[[(3-Methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

1.83 g (12.9 mmol) of methyl iodide was added to a solution of 1.50 g(4.3 mmol) of1-[[(2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 1.78 g (12.9 mmol) of potassium carbonate in 100ml of acetonitrile, and the mixture was heated under reflux overnight.The reaction solution was concentrated, ethyl acetate was added thereto,and the mixture was successively washed with water, a 10% aqueouspotassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel chromatographyto obtain 710 mg (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-1.30 (1H, m), 1.42-1.56 (2H, m), 1.61-1.69 (3H,m), 1.79-1.88 (2H, m), 2.08-2.17 (2H, m), 2.86 (3H, s), 3.40 (2H, t, J=8Hz), 3.81 (2H, t, J=8 Hz), 5.17 (2H, s), 7.30-7.36 (5H, m), 8.55 (1H,br-s)

REFERENCE EXAMPLE 1101-[[(3-Methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid

710 mg (2 mmol) of1-[[(3-methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[[(4-phenyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 78 toobtain 539 mg (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.33 (1H, m), 1.42-1.53 (2H, m), 1.61-1.70 (3H,m), 1.82-1.89 (2H, m), 2.11-2.20 (2H, m), 2.89 (3H, s), 3.46 (2H, dd,J=10 Hz, 8 Hz), 3.91 (2H, dd, J=10 Hz, 8 Hz), 8.66 (1H, br-s)

REFERENCE EXAMPLE 1111-[[(2,5-Dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid methyl ester

472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and311 mg (4.5 mmol) of 2,5-dihydropyrrole was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 698 mg (92%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.38 (1H, m), 1.42-1.53 (2H, m), 1.53-1.69 (3H,m), 1.82-1.92 (2H, m), 2.01-2.10 (2H, m), 3.73 (3H, s), 4.18 (4H, s),4.31 (1H, s), 5.82 (2H, s)

REFERENCE EXAMPLE 1121-[[(2,5-Dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid

698 mg (2.8 mmol) of1-[[(2,5-dihydro-1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference Example 90 toobtain 453 mg (69%) of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.73 (6H, m), 1.92-2.22 (2H, m), 2.24-2.36 (2H,m), 4.23 (4H, br-s), 4.23 (1H, br-s), 5.87 (2H, br-s)

REFERENCE EXAMPLE 1131-[(1H-Pyrrol-1-ylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester

1 g (6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and512 mg (7.6 mmol) of pyrrole was used instead of 1-phenylpiperazine inthe process according to Reference Example 77 to obtain 1.52 g (95%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.36-1.57 (3H, m), 1.65-1.74 (3H, m), 1.91-2.02 (2H,m), 2.08-2.19 (2H, m), 3.74 (3H, s), 5.58 (1H, s), 6.28 (2H, dd, J=2 Hz,1 Hz), 7.19 (2H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1141-[(1H-Pyrrol-1-ylcarbonyl)amino]cyclohexanecarboxylic acid

1.52 g (6 mmol) of1-[[(1H-pyrrol-1-yl)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference Example 90 toobtain 839 mg (58%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.15-1.61 (4H, m), 1.69-1.81 (2H, m), 1.83-1.98(2H, m), 2.08-2.19 (2H, m), 6.12 (2H, s), 6.21 (1H, d, J=2 Hz), 7.42(2H, d, J=2 Hz), 7.88 (1H, dr-s)

REFERENCE EXAMPLE 1151-[(3-Thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid

A solution of 78 mg (0.6 mmol) of N,N-dimethylaminopyridine and 1 g(6.36 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester inmethylene chloride was added to a solution of 1.39 mg (6.36 mmol) ofdi-t-butyl dicarbonate in 10 ml of methylene chloride, and the mixturewas stirred at room temperature for 30 minutes. Thereafter, a solutionof 1.29 g (12.7 mmol) of triethylamine and 680 mg (7.6 mmol) ofthiazolidine in methylene chloride was added, and the mixture wasstirred at room temperature overnight. After the reaction solution wasconcentrated, the residue was dissolved in ethyl acetate, and themixture was washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution and thensaturated brine, followed by drying with anhydrous sodium sulfate. Afterthe solvent was distilled off under reduced pressure, tetrahydrofuranand 1N aqueous sodium hydroxide solution were added to the residue, andthe mixture was heated under reflux for 3 hours. After ether was addedto the reaction solution to wash it, the aqueous layer was neutralizedby concentrated hydrochloric acid and extracted with ethyl acetate.After the obtained organic layer was washed with saturated brine, it wasdried with anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 1.1 g (66%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.08-1.25 (1H, m), 1.36-1.69 (6H, m), 1.82-2.01(3H, m), 2.93 (2H, t, J=7 Hz), 3.59 (2H, t, J=7 Hz), 4.43 (2H, s), 6.44(1H, s), 11.99 (1H, br-s)

REFERENCE EXAMPLE 1161-[[[(2-Furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and2.18 g (18 mmol) of (2-furanylmethyl)methylamine was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 4.27 g (78%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.47 (3H, m), 1.57-1.68 (3H, m), 1.80-1.85 (2H,m), 1.97-2.20 (2H, m), 2.94 (3H, s), 3.71 (3H, s), 4.42 (2H, s), 4.74(1H, s), 6.24 (1H, dd, J=3 Hz, 1 Hz), 6.34 (1H, dd, J=3 Hz, J=3 Hz, 2Hz), 7.37 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1171-[[[(2-Furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid

4.27 g (14 mmol) of1-[[[(2-furanylmethyl)methylamino]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference Example 9.0 toobtain 3.47 g (84%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.12-1.23 (1H, m), 1.38-1.52 (5H, m), 1.58-1.64(2H, m), 1.80-2.22 (2H, m), 2.81 (3H, s), 4.42 (2H, s), 6.03 (1H, s),6.24 (1H, dd, J=3 Hz, 1 Hz), 6.40 (1H, dd, J=3 Hz, 2 Hz), 7.57 (1H, dd,J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 1181-[[(Methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid methylester

472 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and643 mg (6 mmol) of N-methylaniline was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 834 mg (96%) of the title compound.

1H-NMR (CDCl₃, δ): 1.12-1.28 (2H, m), 1.48-1.62 (4H, m), 1.64-1.70 (2H,m), 1.90-1.98 (2H, m), 3.25 (3H, s), 3.74 (3H, s), 4.49 (1H, s),7.26-7.36 (3H, m), 7.43-7.46 (2H, m)

REFERENCE EXAMPLE 1191-[[(Methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid

834 mg (2.87 mmol) of1-[[(methylphenylamino)carbonyl]amino]cyclohexanecarboxylic acid methylester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference Example 90 toobtain 464 mg (59%) of the title compound.

1H-NMR (CDCl₃, δ): 0.96-1.05 (2H, m), 1.19-1.30 (1H, m), 1.50-1.60 (3H,m), 1.70-1.81 (2H, m), 1.96-2.02 (2H, m), 3.31 (3H, s), 4.30 (1H, s),7.26-7.33 (2H, m), 7.44 (1H, t, J=9 Hz), 7.51 (2H, t, J=9 Hz)

REFERENCE EXAMPLE 1201-[[[Methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

2.83 g (18 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and2.18 g (18 mmol) of N-methylbenzylamine was used instead of1-phenylpiperazine in the process according to Reference Example 77 toobtain 4.27 g (78%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-1.38 (3H, m), 1.50-1.63 (3H, m), 1.78-1.85 (2H,m), 1.97-2.03 (2H, m), 2.94 (3H, s), 3.73 (3H, s), 4.49 (2H, s), 4.51(1H, s), 7.25-7.30 (3H, m), 7.35 (2H, dt, J=8 Hz, 1 Hz)

REFERENCE EXAMPLE 1211-[[[Methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic acid

4.27 g (14 mmol) of1-[[[methyl(phenylmethyl)amino]carbonyl]amino]cyclohexanecarboxylic,acid methyl ester was used instead of1-[[[4-(phenylmethyl)-1-piperazinyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester in the process according to Reference Example 90 toobtain 3.54 g (86%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.16-2.04 (1H, m), 1.39-1.47 (5H, m), 1.58-1.65(2H, m), 1.97-2.22 (2H, m), 2.79 (3H, s), 4.44 (2H, s), 6.00 (1H, s),7.21-7.34 (5H, m)

REFERENCE EXAMPLE 1221-[[(2-Oxo-2H-pyran-5-yl)carbonyl]amino]cyclohexanecarboxylic acid

2.37 g (10 mmol) of 5-coumarincarboxylic acid N-hydroxysuccineimideester and a solution of 1.43 g (10 mmol) of 1-aminocyclohexanecarboxylicacid and 3.04 g (30 mmol) of triethylamine in 20 ml of dimethylformamidewere stirred overnight. Ethyl acetate was added to the reactionsolution, and the mixture was washed with a 10% aqueous potassiumhydrogensulfate solution and then saturated brine. After it was driedwith anhydrous sodium sulfate, the solvent was distilled off underreduced pressure to obtain 1.42 g (60%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.30-1.44 (3H, m), 1.44-1.63 (3H, m), 1.95-2.09(4H, m), 5.26 (1H, d, J=9 Hz), 7.62 (1H, d, J=9 Hz), 8.28 (1H, d, J=15Hz), 9.68 (1H, d, J=15 Hz)

REFERENCE EXAMPLE 123 1-[(4-Fluorobenzoyl)amino]cyclohexanecarboxylicacid

Under ice-cooling, a solution of 25.0 g (15.8 mmol) of 4-fluorobenzoylchloride in 30 ml of ether was added dropwise to a mixture solution of22.6 g (15.8 mmol) of 1-aminocyclohexanecarboxylic acid and 25.0 g (23.7mmol) of sodium carbonate in 100 ml of ether and 300 ml of water, andthe mixture was stirred at room temperature overnight. After the etherlayer was separated, the aqueous layer was neutralized by concentratedhydrochloric acid under ice-cooling and the precipitated crystal wascollected by filtration to obtain 27.7 g (66%) of the title compound.

REFERENCE EXAMPLE 1241-[[4-(1-Propyl)piperazin-1-yl]phenylcarbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

2.36 g (8.44 mmol) of 4-[4-(1-propyl)piperazin-1-yl]benzoic acidhydrochloride was used instead of phenylacetyl chloride in the processaccording to Reference Example 1 to obtain 1.79 g (46%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=7 Hz), 1.28-1.40 (1H, m), 1.45-1.61(4H, m), 1.61-1.72 (3H, m), 1.90-1.98 (2H, m), 2.15-2.23 (2H, m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.31 (4H,t, J=5 Hz), 5.16 (2H, s), 6.13 (1H, br-s), 6.89 (2H, d, J=8 Hz),7.25-7.33 (5H, m), 7.68 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1251-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid

1.79 g (3.86 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester was used instead of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 2 to obtain 1.43 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, t, J=8 Hz), 1.39-1.61 (3H, m), 1.65-1.78(4H, m), 1.94-2.03 (3H, m), 2.21-2.41 (2H, m), 2.45-2.54 (2H, m),2.65-2.70 (4H, m), 3.27-3.35 (4H, m), 6.06 (1H, br-s), 6.85 (2H, d, J=8Hz), 7.65 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1261-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

1.00 g (3.57 mmol) of 4-(4-propylpiperazin-1-yl)benzoic acidhydrochloride was used instead of 3-furancarboxylic acid in the processaccording to Reference Example 15 to obtain 602 g (44%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.31-1.40 (1H, m) 1.44-1.58(4H, m), 1.62-1.74 (3H, m), 1.88-1.96 (2H, m), 2.11-2.19 (2H; m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.30 (4H,t, J=5 Hz), 3.72 (3H, s), 6.12 (1H, br-s), 6.89 (2H, dd, J=2 Hz, 7 Hz),7.69 (2H, dd, J=2 Hz, 7 Hz)

REFERENCE EXAMPLE 1271-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester hydrochloride

1 ml of 4N hydrochloric acid/ethyl acetate solution was added to asolution of 120 mg (0.31 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 10 ml of ethyl acetate, and the mixture was stirredat room temperature for 30 minutes. The precipitated crystal wascollected by filtration to obtain 87 mg (66%) of the title compound.

1H-NMR (DMSO-d₆, δ): 0.91 (3H, t, J=8 Hz), 1.21-1.35 (1H, m), 1.47-1.62(5H, m), 1.70-1.81 (4H, m), 2.02-2.10 (2H, m), 3.01-3.14 (4H, m),3.15-3.28 (2H, m), 3.50-3.58 (2H, m), 3.82-4.02 (5H, m), 7.04 (2H, dd,J=2 Hz, 7 Hz), 7.79 (2H, dd, J=2 Hz, 7 Hz), 8.11 (1H, s)

REFERENCE EXAMPLE 1281-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride

3 ml of 4N hydrochloric acid was added to 600 mg (1.55 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester, and the mixture was heated under reflux for 6 hours.The mixture was cooled to room temperature and the precipitated crystalwas collected by filtration to obtain 258 mg (41%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=7 Hz), 1.31-1.43 (1H, m), 1.45-1.56(2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H, m), 2.16-2.25 (2H, m),2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m), 6.65 (1H,br-s), 6.92 (2H, d, J=8 Hz), 7.97 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1291-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester

741 mg (3.57 mmol) of 1-aminocyclohexanecarboxylic acid ethyl esterhydrochloride was used instead of 1-aminocyclohexanecarboxylic acidmethyl ester hydrochloride and 1.00 g (3.57 mmol) of4-(4-propylpiperazin-1-yl)benzoic acid hydrochloride was used instead of3-furancarboxylic acid in the process according to Reference Example 15to obtain 928 mg (65%) of the title compound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.24 (3H, t, J=7 Hz), 1.30-1.41(1H, m), 1.43-1.71 (7H., m), 1.88-1.97 (2H, m), 2.10-2.20 (2H, m), 2.36(1H, t, J=6 Hz), 2.37 (1H, t, J=6 Hz), 3.31 (4H, t, J=5 Hz), 4.18 (4H,t, J=5 Hz), 4.20 (2H, q, J=7 Hz), 6.10 (1H, br-s), 6.89 (2H, dd, J=2 Hz,8 Hz), 7.69 (2H, dd, J=2 Hz, 8 Hz)

REFERENCE EXAMPLE 1301-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester hydrochloride

120 mg (0.3 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester was used instead of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference Example 127 toobtain 114 mg (87%) of the title compound.

1H-NMR (DMSO-d₆, δ): 0.93 (3H, t, J=8 Hz), 1.11 (3H, t, J=7 Hz),1.23-1.32 (1H, m), 1.45-1.55 (5H, m), 1.68-1.80 (4H, m), 2.02-2.10 (2H,m), 3.03-3.18 (6H, m), 3.51-3.62 (2H, m), 3.95-4.04 (2H, m), 4.02 (2H,q, J=7 Hz), 7.04 (2H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 8.10 (1H, s)

REFERENCE EXAMPLE 1311-[[[4-(4-Propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride

800 mg (1.99 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester was used instead of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in the process according to Reference Example 128 toobtain 197 mg (24%) of the title compound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=7 Hz), 1.31-1.43 (1H, m), 1.45-1.56(2H, m), 1.64-1.78 (3H, m), 1.90-2.02 (4H, m), 2.16-2.25 (2H, m),2.95-3.28 (5H, m), 3.60-3.75 (4H, m), 3.78-3.89 (2H, m), 6.65 (1H,br-s), 6.92 (2H, d, J=8 Hz), 7.97 (2H, d, J=8 Hz)

EXAMPLE 1 2-(Phenylmethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 784 mg (3 mmol) of1-[(phenylacetyl)amino]cyclohexanecarboxylic acid obtained in ReferenceExample 2 in 20 ml of methylene chloride. After the mixture was stirredat room temperature for 4 hours, the reaction solution was concentratedunder reduced pressure, ethyl acetate was added thereto, and the mixturewas successively washed with water, a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtain625 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 1.48-1.51 (1H, m), 1.56-1.70 (3H, m), 1.70-1.79 (6H,m), 3.79 (2H, s), 7.28-7.36 (5H, m)

EXAMPLE 2 2-(2-Phenylethyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

826 mg (3 mmol) of 1-[(1-oxo-3-phenylpropyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 764 mg (99%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.47-1.55 (4H, m), 1.57-1.78 (6H, m), 2.79 (2H, t,J=7 Hz), 3.02 (2H, t, J=7 Hz), 7.20-7.23 (3H, m), 7.28-7.31 (2H, m)

EXAMPLE 3 2-(4-Biphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

970 mg (3 mmol) of 1-[(4-biphenylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 914 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.52 (2H, m), 1.63-1.71 (1H, m), 1.72-1.80 (2H, m),1.81-1.90 (5H, m), 7.39-7.42 (1H, m), 7.47-7.50 (2H, m), 7.63 (1H, dd,J=7 Hz, 1 Hz), 7.65 (1H, dd, J=7 Hz, 1 Hz), 7.71 (1H, d, J=7 Hz, 1 Hz),7.72 (1H, dd, J=7 Hz, 1 Hz), 8.07 (1H, dd, J=7 Hz, 1 Hz), 8.08 (1H, dd,J=7 Hz, 1 Hz)

EXAMPLE 4 2-(2-Naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

595 mg (2 mmol) of 1-[(2-naphthylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 562 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.54-1.68 (1H, m), 1.69-1.76 (1H, m), 1.78-1.94 (8H,m), 7.26-7.62 (2H, m), 7.89 (1H, d, J=8 Hz), 7.92 (1H, dd, J=8 Hz, 1Hz), 7.95 (1H, dd, J=8 Hz, 1 Hz), 8.09 (1H, dd, J=8 Hz, 1 Hz), 8.49 (1H,d, J=1 Hz)

EXAMPLE 5 2-(1-Naphthyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.35 g (3.5 mmol) of 1-[(1-naphthylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester obtained in Reference Example 11 was dissolvedin 50 ml of methanol, 150 mg of 10% palladium-carbon was added thereto,and the mixture was stirred under a hydrogen atmosphere at roomtemperature overnight. After the reaction solution was filtered; thefiltrate was concentrated under reduced pressure. The obtained residuewas dissolved in 30 ml of methylene chloride, and 633 mg (3.3 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was addedthereto. After the mixture was stirred at room temperature for 4 hours,the reaction solution was concentrated under reduced pressure, ethylacetate was added thereto, and the mixture was successively washed withwater, a 10% aqueous potassium hydrogensulfate solution, a saturatedaqueous sodium hydrogencarbonate solution and saturated brine, followedby drying with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain 738 mg (88%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.68 (3H, m), 1.70-2.00 (7H, m), 7.53-7.60 (2H,m), 7.67 (1H, td, 7 Hz, 1 Hz), 7.92 (1H, dd, J=7 Hz, 1 Hz), 8.03 (1H, d,J=7 Hz), 8.17 (1H, dd, J=7 Hz, 1 Hz), 9.33 (1H, dd, J=7 Hz, 1 Hz)

EXAMPLE 62-[(RS)-2,3-Tetrahydrobenzofuran-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

868 mg (3 mmol) of1-[[[(RS)-2,3-tetrahydrobenzofuran-2-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 686 mg (87%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.43-1.82 (10H, m), 3.56 (2H, d, J=9 Hz), 5.46 (1/2H,d, J=10 Hz), 5.48 (1/2H, d, J=10 Hz), 6.89 (1H, td, 8 Hz, 1 Hz), 6.93(1H, dd, H=8 Hz, 1 Hz), 7.16 (1H, td, J=8 Hz, 1 Hz), 7.21 (1H, dd, J=8Hz, 1 Hz)

EXAMPLE 7 2-(2-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

53.2 g (224 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 49.8 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.57 (1H, m), 1.66-1.86 (9H, m), 6.58 (1H, dd,J=4 Hz, 2 Hz), 7.09 (1H, dd, J=4 Hz, 1 Hz), 7.65 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 8 2-(3-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.48 g (18.9 mmol) of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 4.02 g (97%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.54-1.57 (1H, m), 1.63-1.86 (9H, m), 6.86 (1H, dd,J=2 Hz, 1 Hz), 7.51 (1H, t, J=2 Hz), 7.99 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 9 2-[2-(2-Furanyl)ethenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

10.0 g (38 mmol) of1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Example 1 to obtain 8.92 g (96%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.26-1.54 (2H, m), 1.66-1.84 (8H, m), 6.48 (1H, dd,J=2 Hz, 1 Hz), 6.53 (1H, d, J=16 Hz), 6.60 (1H, d, J=2 Hz), 7.22 (1H, d,J=16 Hz), 7.51 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 10 2-Cyclohexyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.15 g (16.3 mmol) of 1-[(cyclohexylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 3.75 g (98%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.24-1.38 (3H, m), 1.44-1.56 (3H, m), 1.56-1.63 (3H,m), 1.63-1.84 (9H, m), 1.92-2.00 (2H, m), 2.43-2.49 (1H, m)

EXAMPLE 11 2-(6-Benzothiazolyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

365 mg (1.2 mmol) of1-[(6-benzothiazolylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 287 mg (83%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.53-1.62 (4H, m), 1.68-1.79 (2H, m), 1.81-1.92 (4H,m), 8.19 (1H, dd, J=9 Hz, 2 Hz), 8.22 (1H, dd, J=9 Hz, 1 Hz), 8.65 (1H,dd, J=2 Hz, 1 Hz), 9.15 (1H, s)

EXAMPLE 12 2-(2-Thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

5.0 g (20 mmol) of 1-[(2-thienylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 4.46 g (96%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.59 (1H, m), 1.61-1.69 (1H, m), 1.71-1.88 (8H,m), 7.14 (1H, dd, J=5 Hz, 4 Hz), 7.57 (1H, dd, J=5 Hz, 1 Hz), 7.70 (1H,dd J=4 Hz, 1 Hz)

EXAMPLE 13 2-(2-Furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to asolution of 10 g (42 mmol) of1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained inReference Example 14 and 6.1 ml (44 mmol) of triethylamine intetrahydrofuran (80 ml), and the mixture was stirred at room temperaturefor 1 hour. The precipitated crystal was removed by filtration and thefiltrate was concentrated. The obtained crystal was washed with water toobtain 8.95 g (97%) of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.57 (1H, m), 1.66-1.86 (9H, m), 6.58 (1H, dd,J=4 Hz, 2 Hz), 7.09 (1H, dd, J=4 Hz, 1 Hz), 7.65 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 14 2-(1,3-Benzodioxol-5-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

5.8 g (20 mmol) of1-[[(1,3-benzodioxole)-5-carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 4.9 g (90%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.51-1.57 (1H, m), 1.63-1.75 (3H, m), 1.76-1.88 (6H,m), 6.05 (2H, s), 6.87 (1H, d, J=8 Hz), 7.46 (1H, d, J=2 Hz), 7.55 (1H,dd, J=8 Hz, 2 Hz)

EXAMPLE 15 2-(2-Benzofuranyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

3.8 g (13 mmol) of1-[[(2-benzofuranyl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 3.4 g (96%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.51-1.74 (2H, m), 1.78-1.94 (8H, m), 7.33 (1H, ddd,J=8 Hz, 7 Hz, 1 Hz), 7.44 (1H, d, J=1 Hz), 7.46 (1H, ddd, J=8 Hz, 7 Hz,1 Hz), 7.63 (1H, ddd, J=8 Hz, 2 Hz, 1 Hz), 7.70 (1H, ddd, J=8 Hz, 2 Hz,1 Hz)

EXAMPLE 16 2-(2-Pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

511 mg (2 mmol) of 1-[(2-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 405 mg (85%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.54-1.77 (3H, m), 1.78-1.92 (7H, m), 7.62 (1H, ddd,J=7 Hz, 5 Hz, 2 Hz), 7.87 (1H, dt, J=7 Hz, 2 Hz), 8.04 (1H, dd, J=5 Hz,2 Hz), 8.82 (1H, dd, J=5 Hz, 2 Hz)

EXAMPLE 17 2-(3-Thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

253 mg (1 mmol) of 1-[(3-thienylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 234 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.52-1.87 (10H, m), 7.40 (1H, dd, J=5 Hz, 3 Hz), 7.60(1H, dd, J=5 Hz, 1 Hz), 8.00 (1H, dd, J=3 Hz, 1 Hz)

EXAMPLE 18 2-(3-Ethoxy-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

327 mg (1 mmol) of1-[[(3-ethoxy-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 307 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.46 (3H, t, J=7 Hz), 1.49-1.84 (10H, m), 4.22 (2H,q, J=7 Hz), 6.86 (1H, d, J=6 Hz), 7.42 (1H, d, J=6 Hz)

EXAMPLE 19 2-[2-[(S)-1-Phenylethyl]]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

275 mg (1 mmol) of1-[[(S)-1-oxo-2-phenylpropyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 257 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.78 (13H, m), 3.89 (1H, q, J=7 Hz), 7.26-7.35(5H, m)

EXAMPLE 20 2-(2-Pyradinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1 mmol) of 1-[(2-pyrazinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 231 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.56-1.93 (10H, m), 8.78 (2H, m), 9.28 (1H, t, J=3Hz)

EXAMPLE 21 2-(5-Methylisoxazol-4-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1 g (7.87 mmol) of 5-methylisoxazole-4-carboxylic acid was added to 3 mlof thionyl chloride, and the mixture was stirred overnight. The reactionsolution was concentrated under reduced pressure, and the obtainedresidue was added to a solution of 1.13 g (7.87 mmol) of1-aminocyclohexanecarboxylic acid and 6.6 g (79 mmol) of sodiumhydrogencarbonate in 30 ml of toluene-30 ml of water. After the mixturewas stirred at room temperature overnight, the toluene layer wasseparated. The aqueous layer was neutralized by potassiumhydrogensulfate and extracted with ethyl acetate. After the obtainedorganic layer was washed with saturated brine, it was dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, methylene chloride was added thereto, and under ice-cooling,332 mg (1.73 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added. After the mixture was stirred at roomtemperature overnight, the reaction solution was concentrated underreduced pressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine, followed by drying with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain 295 mg (16%)of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.59 (1H, m), 1.64-1.72 (2H, m), 1.76-1.83 (7H,m), 2.75 (3H, s), 8.55 (1H, s)

EXAMPLE 22 2-Cyclopentyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.98 g (15 mmol) of cyclopentanecarbonyl chloride was added to asolution of 2.16 g (15 mmol) of 1-aminocyclohexanecarboxylic acid and4.8 g (45 mmol) of sodium carbonate in 50 ml of ethyl acetate-50 ml ofwater under ice-cooling. After the mixture was stirred at roomtemperature overnight, ethyl acetate was added thereto, and the mixturewas washed with a 10% aqueous potassium hydrogensulfate solution, asaturated aqueous sodium bicarbonate solution and then saturated brine.After the obtained organic layer was washed with saturated brine, it wasdried with anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, methylene chloride was added thereto, and 1.59 g (8.3mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride wasadded under ice-cooling. After the mixture was stirred at roomtemperature overnight, the reaction solution was concentrated underreduced pressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine, followed by drying with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain 1.41 g (42%)of the title compound.

1H-NMR (CDCl₃, δ): 1.53-1.65 (5H, m), 1.67-1.76 (4H, m), 1.86-1.95 (8H,m), 2.80-2.89 (2H, m)

EXAMPLE 23 2-(5-Methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

294 mg (1.1 mmol) of1-[[(5-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 273 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.53-1.62 (3H, m), 1.71-1.84 (7H, m), 2.55 (3H, s),6.79 (1H, d, J=3 Hz), 7.50 (1H, d, J=3 Hz)

EXAMPLE 24 2-(4-Methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

305 mg (1.1 mmol) of1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 288 mg (90%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.51-1.60 (1H, m), 1.61-1.73 (3H, m), 1.76-1.90 (6H,m), 3.87 (3H, s), 6.96 (2H, dd, J=7 Hz, 2 Hz), 7.94 (2H, dd, J=7 Hz, 2Hz)

EXAMPLE 25 2-(3-Methyl-2-thienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1.1 mmol) of1-[[(3-methyl-2-thienyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 249 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.50-1.60 (1H, m), 1.65-1.78 (3H, m), 1.78-1.90 (6H,m), 2.58 (3H, s), 6.95 (1H, d, J=5 Hz), 7.42 (1H, d, J=5 Hz)

EXAMPLE 26 2-(3-Methyl-2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

902 mg (3.59 mmol) of1-[[(3-methyl-2-furanyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 233 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.48-1.61 (1H, m), 1.62-1.89 (9H, m), 2.36 (3H, s),6.40 (1H, d, J=1 Hz), 7.52 (1H, d, J=1 Hz)

EXAMPLE 27 2-(3-Pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

523 mg (2.11 mmol) of1-[(3-pyridinylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 486 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.50-1.90 (10H, m), 7.42 (1H, dd, J=8 Hz, 5 Hz), 8.27(1H, d, J=8 Hz), 8.78 (1H, d, J=5 Hz), 9.00 (1H, s)

EXAMPLE 282-(1-Methyl-1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

187 mg (0.75 mmol) of1-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Example 1 to obtain 172 mg (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.44-1.85 (10H, m), 3.40 (3H, s), 6.18 (1H, dd, J=4Hz, 3 Hz), 6.82-6.86 (2H, m)

EXAMPLE 29 2-[(R)-1-Phenylethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

303 mg (1.1 mmol) of1-[((R)-1-oxo-2-phenylpropyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 257 mg (90%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.45-1.65 (7H, m), 1.67-1.80 (6H, m), 3.89 (1H, q,J=7 Hz), 7.26-7.34 (5H, m)

EXAMPLE 30 2-(1H-Indol-5-ylcarbonyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

329 mg (1.2 mmol) of1-[(1H-indol-5-ylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 258 mg (80%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.56-1.89 (10H, m), 6.65 (1H, dd, J=3 Hz, 2 Hz),7.26-7.36 (1H, m), 7.46 (1H, d, J=9 Hz), 7.88 (1H, dd, J=9 Hz, 2 Hz),8.32 (1H, s), 8.35 (1H, br-s)

EXAMPLE 312-(1-Cyclopentenylcarbonyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

237 mg (1 mmol) of1-[(1-cyclopentenylcarbonyl)amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 219 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.53-1.82 (10H, m), 1.99-2.10 (2H, m), 2.55-2.69 (2H,m), 2.69-2.80 (2H, m), 6.65-6.67 (1H, m)

EXAMPLE 32 2-(4-Pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

552 mg (2.2 mmol) of 1-[(4-pyridinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 450 mg (88%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.50-1.92 (10H, m), 7.85 (2H, dd, J=5 Hz, 2 Hz), 8.80(2H, dd, J=5 Hz, 2 Hz)

EXAMPLE 33 2-(1H-Pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

200 mg (0.85 mmol) of1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 184 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.51-1.65 (1H, m), 1.65-1.86 (9H, m), 6.32 (1H, dd,J=4 Hz, 2 Hz), 6.87 (1H, dd, J=4 Hz, 2 Hz), 7.01 (1H, dd, J=4 Hz, 2 Hz),9.37 (1H, br-s)

EXAMPLE 34 2-(6-Hydroxy-2-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(6-hydroxy-2-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 250 mg (97%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.52 (1H, m), 1.78 (9H, m), 6.85-6.79 (2H, m), 7.50(1H, dd, J=9 Hz, 7 Hz)

EXAMPLE 35 2-(2-Hydroxy-3-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(2-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 257 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.04-2.21 (10H, m), 6.40-6.50 (1H, m), 7.69-7.82 (1H,m), 8.28-8.35 (1H, m)

EXAMPLE 36 2-(6-Hydroxy-3-pyridinyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

278 mg (1 mmol) of1-[[(6-hydroxy-3-pyridinyl)carbonyl]amino]cyclohexanecarboxylic acid wasused instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 257 mg (quantitative) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.45-1.86 (10H, m), 6.66 (1H, d, J=10 Hz), 8.02 (1H,d, J=2 Hz), 8.05 (1H, dd, J=10 Hz, 2 Hz)

EXAMPLE 37 2-[2-(2-Furanyl)ethyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.7 ml of 2N aqueous NaOH solution was added to a solution of 478 mg(1.7 mmol) of 1-[[1-oxo-3-(2-furanyl)propyl]amino]cyclohexanecarboxylicacid methyl ester obtained in Reference Example 64 in 2 ml oftetrahydrofuran, and the mixture was heated under reflux for 3 hours.Ether was added to the reaction solution to wash it. After the separatedaqueous layer was neutralized with concentrated hydrochloric acid, itwas extracted with ethyl acetate. After the obtained organic layer waswashed with saturated brine, it was dried with anhydrous sodium sulfateand the solvent was distilled off under reduced pressure. Then, 10 ml ofmethylene chloride and 377 mg (1.82 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred at room temperatureovernight. The solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and then saturated brine, followed by dryingwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 198 mg (47%) of the title compound.

1H-NMR (CDCl₃, δ): 1.43-1.60 (4H, m), 1.60-1.80 (6H, m), 2.84 (2H, t,J=7 Hz), 3.05 (2H, t, J=7 Hz), 6.06 (1H, dd, J=2 Hz, 1 Hz), 6.27 (1H,dd, J=2 Hz, 1 Hz), 7.31 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 382-[1-[(2-Propoxy)carbonyl]piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

940 mg (2.76 mmol) of1-[[[1-(2-propoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 818 mg (92%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.24 (6H, d, J=6 Hz), 1.44-1.79 (12H, m) 1.90-1.98(2H, m), 2.62-2.69 (1H, m), 2.89-2.99 (2H, m), 4.03-4.19 (2H, m),4.88-4.97 (1H, m)

EXAMPLE 392-[1′-(Ethoxycarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

935 mg (2.86 mmol) of1-[[[1-(ethoxycarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 730 mg (83%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.45-1.80 (12H, m), 1.92-1.99(2H, m), 2.62-2.70 (1H, m), 2.90-3.03 (2H, m), 4.03-4.20 (4H, m)

EXAMPLE 402-[1-(2-Furanylcarbonyl)piperidin-4-yl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

196 mg (0.56 mmol) of1-[[[1-(2-furanylcarbonyl)piperidin-4-yl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 185 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.49-1.68 (5H, m), 1.68-1.80 (5H, m), 1.80-1.92 (2H,m), 2.03-2.10 (2H, m), 2.75-2.83 (1H, m), 3.05-3.31 (2H, m), 4.28-4.40(2H, m), 6.48 (1H, dd, J=3 Hz, 1 Hz), 7.00 (1H, dd, J=3 Hz, 1 Hz), 7.48(1H, dd, J=3 Hz, 1 Hz)

EXAMPLE 412-[[(2-Furanylcarbonyl)amino]methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

249 mg (1 mmol) of1-[[[(2-furanylcarbonyl)amino]acetyl]amino]cyclohexanecarboxylic acidwas used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid inthe process according to Example 1 to obtain 276 mg (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.50-1.80 (10H, m), 4.45 (2H, d, J=6 Hz), 6.53 (1H,dd, J=3 Hz, 1 Hz), 6.90 (1H, br-s), 7.18 (1H, ddd, J=3 Hz, 2 Hz, 1 Hz),7.50 (1H, dd, J=2 Hz, 1 Hz)

EXAMPLE 42 2-[(Benzoylamino)methyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

724 mg (2.26 mmol) of1-[[(benzoylamino)acetyl]amino]cyclohexanecarboxylic acid was usedinstead of 1-[(phenylacetyl)amino]cyclohexanecarboxylic acid in theprocess according to Example 1 to obtain 631 mg (97%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.48-1.58 (1H, m), 1.63-1.80 (9H, m), 4.49 (2H, d,J=5 Hz), 6.76 (1H, br-s), 7.48 (2H, m), 7.55 (1H, m), 7.83 (2H, m)

EXAMPLE 43 2-(4-Fluorophenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

After a suspension of 13.3 g (50 mmol) of1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid in 30 ml of aceticanhydride was stirred at 100° C. for 30 minutes, the reaction solutionwas concentrated under reduced pressure. Toluene was added to theresidue, and the mixture was washed with water, a saturated aqueoussodium hydrogencarbonate solution and then saturated brine. After theorganic layer was dried with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography to obtain 8.5 g (69%) of the title compound.

1H-NMR (CDCl₃, δ): 1.49-1.60 (1H, m), 1.63-1.90 (9H, m), 7.13-7.20 (2H,m), 8.00-8.05 (2H, m)

EXAMPLE 442-[[4-(1-Propyl)piperazin-1-yl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

1.43 g (3.86 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of 1-[(phenylacetyl)amino]cyclohexanecarboxylicacid in the process according to Example 1 to obtain 1.33 g (98%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.50-1.61 (3H, m), 1.61-1.69(1H, m), 1.69-1.76 (2H, m), 1.79-1.84 (6H, m), 2.35 (1H, t, J=6 Hz),2.36 (1H, t, J=6 Hz), 2.59 (4H, t, J=5 Hz), 3.35 (4H, t, J=5 Hz), 6.91(2H, dd, J=2 Hz, 7 Hz), 7.86 (2H, dd, J=2 Hz, 7 Hz)

EXAMPLE 452-[4-(4-Propylpiperazin-1-yl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onehydrochloride

631 mg (1.54 mmol) of1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid hydrochloride was used instead of1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid in the processaccording to Example 43 to obtain 500 mg (83%) of the title compound.

1H-NMR (CDCl₃, δ): 1.05 (3H, t, J=8 Hz), 1.50-1.87 (10H, m), 1.95-2.06(2H, m), 2.86-3.01, (4H, m), 3.59-3.68 (2H, m), 3.79-3.90 (4H, m), 6.91(2H, dd, 2 Hz, 7 Hz), 7.91 (2H, dd, J=2 Hz, 7 Hz)

REFERENCE EXAMPLE 132N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

After 422 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 555 mg (2 mmol) of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, 322 mg(2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in20 ml of methylene chloride under ice-cooling, the mixture was stirredat room temperature for 18 hours. The reaction solution was concentratedunder reduced pressure, ethyl acetate was added to the residue, and themixture was washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution and thensaturated brine. The organic layer was dried with anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 662mg (91%) of the title compound.

1H-NMR (CDCl₃, δ): 0.87 (3H, d, J=7 Hz), 0.92 (3H, d, J=7 Hz), 1.28-1.46(3H, m), 1.52-1.70 (3H, m), 1.73-1.82 (1H, m), 1.85-2.03 (4H, m), 2.76(1H, br-s), 3.42-4.47 (1H, m), 3.65-3.74 (2H, m), 5.02-5.16 (3H, m),6.36 (1H, d, J=8 Hz), 7.30-7.40 (5H, m)

REFERENCE EXAMPLE 133N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinol

234 mg (2 mmol) of L-norleucinol was used instead of L-valinol in theprocess according to Reference Example 132 to obtain 350 mg (75%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 1.23-1.52 (9H, m), 1.58-1.70(3H, m), 1.83-2.04 (4H, m), 2.83 (1H, br-s), 3.34-3.40 (1H, m), 3.70(1H, br-s), 3.89 (1H, br-s), 5.02-5.13 (3H, m), 6.26 (1H, d, J=8 Hz),7.31-7.40 (5H, m)

REFERENCE EXAMPLE 134N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

A solution of 8.81 ml (50.6 mmol) of N,N-diisopropylethylamine, and 2.09g (20.2 mmol) of L-valinol in 10 mL of methylene chloride was added to asolution of 3.71 g (16.9 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 100 ml of toluene,and the mixture was heated under reflux for 14 hours. The reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded to the residue, and the mixture was washed with water, a 10%aqueous potassium hydrogensulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and then saturated brine. The organic layerwas dried with anhydrous sodium sulfate and the solvent was distilledoff under reduced pressure. Ethyl acetate was added to the residue, andthe mixture was stirred overnight. The obtained crystal was collected byfiltration to obtain 4.06 g (74.7%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz), 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 135N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

Under an argon atmosphere, 72 mg (0.59 mmol) of isopropylchlorocarbonate was added to a solution of 200 mg (0.59 mmol) ofN-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine and 60 mg(0.59 mmol) of triethylamine in 2 ml of tetrahydrofuran underice-cooling. After the mixture was stirred at 0° C. for 2 hours, thereaction solution was filtered and poured to a solution of 45 mg (1.2mmol) of sodium borohydride in 1 ml of water, and the mixture wasstirred overnight. Ethyl acetate was added to the reaction solution, andthe mixture was successively washed with a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine, followed by drying with sodium sulfate.After the solvent was distilled off under reduced pressure, the obtainedcrystal was washed with ether to obtain 30 mg (16%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz), 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 136N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

Under an argon atmosphere, 31 mg (0.82 mmol) of lithium aluminum hydridewas added to 1 ml of diethyl ether placed in a flask. Under ice-cooling,a solution of 0.3 g (0.82 mmol) of the above compound in 1 ml oftetrahydrofuran was added to the flask, and the mixture was stirred for1 hour and 30 minutes. Ice-water was added to the reaction solution.Ethyl acetate was added thereto, and the mixture was successively washedwith a 10% aqueous potassium hydrogensulfate solution, a saturatedaqueous sodium hydrogencarbonate solution and saturated brine. After itwas dried with sodium sulfate, the solvent was distilled off underreduced pressure. The obtained crystal was washed with ether to obtain155 mg (60%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz), 1.32-1.56(3H, m), 1.58-1.76 (3H, m), 1.80-1.90 (1H, m), 1.96-2.08 (2H, m),2.14-2.24 (2H, m), 3.00-3.06 (1H, m), 3.52-3.58 (1H, m), 3.68-3.78 (2H,m), 6.49 (1H, s), 6.53 (1H, dd, J=4 Hz, 2 Hz), 6.75-6.77 (1H, m), 7.14(1H, dd, J=4 Hz, 1 Hz), 7.49 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 137N-[[1-[(4-Morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinol

513 mg (2 mmol) of 1-[(4-morpholinylcarbonyl)amino]cyclohexanecarboxylicacid was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid in theprocess according to Reference Example 132 to obtain 215 mg (30%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.26-1.56 (9H, m), 1.60-1.73(3H, m), 1.85-2.05 (4H, m), 3.33-3.43 (5H, m), 3.54 (1H, t, J=7 Hz),3.66-3.73 (4H, m), 3.76-3.82 (1H, m), 3.83-3.93 (1H, m), 4.64 (1H,br-s), 6.35 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 138 N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-valinol

N-[(phenylmethoxy)carbonyl]-L-leucine was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid in theprocess according to Reference Example 132 to obtain 659 mg (94%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.83-0.99 (12H, m), 1.46-1.74 (3H, m), 1.78-1.90 (1H,m), 2.42 (1H, br-s), 3.57-3.72 (3H, m), 4.10-4.17 (1H, m), 5.04-5.17(3H, m), 6.22 (1H, d, J=7 Hz), 7.27-7.39 (5H, m)

REFERENCE EXAMPLE 139N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol

N-[(phenylmethoxy)carbonyl]-L-leucine was used instead of1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid andL-norleucinol was used instead of L-valinol in the process according toReference Example 132 to obtain 421 mg (58%) of the title compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 0.95 (6H, d, J=7 Hz), 1.23-2.72(9H, m), 2.44 (1H, br-s), 3.47-3.71 (2H, m), 3.89 (1H, br-s), 4.10-4.17(1H, m), 5.08-5.16 (3H, m), 6.10 (1H, d, J=6 Hz), 7.31-7.39 (5H, m)

REFERENCE EXAMPLE 140N—[N-(4-Morpholinylcarbonyl)-L-leucyl]-L-norleucinol

70 mg of 10% palladium-carbon was added to a solution of 700 mg (2 mmol)of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol obtained inReference Example 139 in 10 ml of methanol, and the mixture was stirredunder a hydrogen atmosphere at room temperature overnight. After thereaction solution was filtered, the filtrate was concentrated underreduced pressure. 20 ml of methylene chloride and 404 mg (4 mmol) oftriethylamine were added to the residue. A solution of 299 mg (2 mmol)of 4-morpholinecarbonyl chloride in 3 ml of methylene chloride was addedto the mixture solution under ice-cooling. The reaction solution wasreturned to room temperature and stirred overnight. After the reactionsolution was washed with water and then saturated brine, it was driedwith anhydrous sodium sulfate and the solvent was distilled off underreduced pressure. Ether was added to the residue to wash it to obtain488 mg (71%) of the title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 0.94 (3H, d, J=7 Hz), 0.96 (3H,d, J=7 Hz), 1.23-1.37 (4H, m), 1.43-1.72 (5H, m), 2.67 (1H, br-s),3.31-3.44 (4H, m), 3.52-3.60 (1H, m), 3.65-3.73 (5H, m), 3.82-3.89 (1H,m), 4.24-4.32 (1H, m), 4.82 (1H, d, J=8 Hz), 6.31 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 141 N—[N-(2-Furanylcarbonyl)-L-leucyl]-L-valinol

30 mg of 10% palladium-carbon was added to a solution of 350 mg (1 mmol)of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinol obtained inReference Example 139 in 10 ml of methanol, and the mixture was stirredunder a hydrogen atmosphere at room temperature overnight. After thereaction solution was filtered, the filtrate was concentrated underreduced pressure. 10 ml of ethyl acetate, 10 ml of water and further 159mg (1.5 mmol) of sodium carbonate were added to the residue. A solutionof 131 mg (1 mmol) of 2-furancarbonyl chloride in 3 ml of ethyl acetatewas added to the mixture solution under ice-cooling. The reactionsolution was returned to room temperature and was stirred overnight. Theaqueous layer of reaction solution was separately collected andextracted with ethyl acetate. The organic layer was combined and afterit was washed with 10% potassium hydrogensulfate and then saturatedbrine, it was dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, ether was added to the residue andthe crystal was washed to obtain 268 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz), 0.97 (3H,t, J=7 Hz), 0.99 (3H, t, J=7 Hz), 1.65-1.94 (4H, m), 2.47 (1H, t, J=5Hz), 3.63-3.74 (3H, m), 4.54-4.62 (1H, m), 6.42 (1H, d, J=7 Hz), 6.52(1H, dd, J=4 Hz, 2 Hz), 6.68 (1H, d, J=8 Hz), 7.14 (1H, dd, J=4 Hz, 1Hz), 7.47 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 142N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine ethylester

30 ml of dimethylformamide was added to a flask in which 5 g (27 mmol)of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one were placed. Then,3.53 g (27.4 mmol) of diisopropylethylamine was added thereto, and themixture was stirred for 3 days. After the solvent was distilled offunder reduced pressure, ethyl acetate was added thereto, and the mixturewas successively washed with a 10% aqueous potassium hydrogensulfatesolution and saturated brine, followed by drying with sodium sulfate.After the solvent was distilled off under reduced pressure, it waspurified by silica gel chromatography to obtain 8.3 g (quantitative) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.25 (3H,t, J=7 Hz), 1.35-1.70 (6H, m), 1.98-2.01 (2H, m), 2.19-2.23 (2H, m),2.31-2.39 (1H, m), 4.11-4.19 (2H, m), 4.49 (1H, dd, J=9 Hz, 5 Hz), 6.34(1H, s), 6.53 (1H, dd, J=3 Hz, 1 Hz), 7.15 (1H, dd, J=3 Hz, 1 Hz), 7.48(1H, dd, J=2 Hz, 1 Hz), 7.58 (1H, d, J=9 Hz)

REFERENCE EXAMPLE 143N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine

10 ml of N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valineand 2.0 g (9.1 mmol) of2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture wasstirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, ethyl acetate was added thereto,and the mixture was washed with a 10% aqueous potassium hydrogensulfatesolution and then saturated brine, followed by drying with anhydroussodium sulfate. The solvent was distilled off under reduced pressure andit was purified by silica gel chromatography to obtain 384 mg (12.5%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.97 (3H, d, J=7 Hz), 1.33-1.48(3H, m), 1.64-1.73 (3H, m), 1.98 (2H, dt, J=14 Hz, 4 Hz), 2.22-2.30 (3H,m), 4.46 (1H, m), 6.43 (1H, s), 6.53 (1H, dd, J=3 Hz, 2 Hz), 7.17 (1H,dd, J=3 Hz, 1 Hz), 7.48 (1H, dd, J=2 Hz, 1 Hz), 7.55 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 144N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

Under an argon gas atmosphere, 1.22 g (9.44 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 1.50 g(9.44 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, a solution of 570 mg (1.57 mmol) ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol in3 ml of anhydrous dimethyl sulfoxide was added to the reaction solution,and the mixture was stirred at the same temperature for 2 hours. Thereaction solution was poured to ice-water and extracted with ethylacetate twice. After the organic layer was washed with a 10% aqueouscitric acid solution, a saturated aqueous sodium hydrogencarbonatesolution and then saturated brine and dried with anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. 20 ml ofdiisopropyl ether was added to the residue, and the mixture was stirredat room temperature for 18 hours. The obtained crystal was collected byfiltration to obtain 435 mg (77%) of the title compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, d, J=7 Hz), 0.97 (3H, d, J=7 Hz), 1.22-1.44(3H, m), 1.59-1.70 (3H, m), 1.85-2.15 (4H, m), 2.22-2.34 (1H, m), 4.48(1H, s), 4.96 (1H, s), 5.11 (2H, s), 7.10-7.41 (6H, m), 9.59 (1H, s)

REFERENCE EXAMPLE 145N-[[1-[[(Phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinal

465 mg (1.24 mmol) ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-norleucinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 350 mg (75%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.88 (3H, d, J=7 Hz), 1.19-1.43 (7H, m), 1.51-1.70(4H, m), 1.82-2.13 (5H, m), 4.42 (1H, br-s), 4.95 (1H, s), 5.10 (2H, s),7.10 (1H, br-s), 7.29-7.42 (5H, m), 9.53 (1H, s)

REFERENCE EXAMPLE 146N-[[1-[(2-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal

3.50 g (10.9 mmol) ofN-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol was usedinstead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 3.14 g (90.3%)of the title compound.

1H-NMR (CDCl₃, δ): 0.94 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.30-1.40(1H, m), 1.41-1.54 (2H, m), 1.62-1.76 (3H, m), 1.95-2.04 (2H, m),2.20-2.26 (1H, m), 2.28-2.36 (2H, m), 4.44 (1H, dd, J=8 Hz, 5 Hz), 6.38(1H, br-s), 6.54 (1H, dd, J=4 Hz, 2 Hz), 7.15 (1H, dd, J=4 Hz, 1 Hz),7.49 (1H, dd, J=2 Hz, 1 Hz), 7.68 (1H, d, J=8 Hz), 9.60 (1H, s)

REFERENCE EXAMPLE 147N-[[1-[(4-Morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinal

205 mg (0.58 mmol) ofN-[[1-[(4-morpholinylcarbonyl)amino]cyclohexyl]carbonyl]-L-norleucinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 125 mg (61%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.23-1.42 (7H, m) 1.52-1.71(4H, m), 1.83-1.98 (3H, m), 2.05-2.18 (2H, m), 3.34-3.42 (4H, m),3.65-3.76 (4H, m), 4.37 (1H, dt, J=7 Hz, 7 Hz), 4.48 (1H, s), 7.81 (1H,d, J=7 Hz), 9.55 (1H, s)

REFERENCE EXAMPLE 148 N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-valinal

280 mg (0.8 mmol) of N—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinolwas used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 278 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.83-1.01 (12H, m), 1.48-1.59 (1H, m), 1.62-1.74 (2H,m), 2.28-2.37 (1H, m), 4.19-4.28 (1H, m), 4.51-4.56 (1H, m), 5.05-5.17(3H, m), 6.51 (1H, d, J=7 Hz), 7.27-7.39 (5H, m), 9.64 (1H, s)

REFERENCE EXAMPLE 149N—[N-[(Phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinal

253 mg (0.7 mmol) ofN—[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-norleucinol was used insteadof N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolin the process according to Reference Example 144 to obtain 195 mg (78%)of the title compound.

1H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 0.95 (6H, d, J=7 Hz), 1.22-1.39(4H, m), 1.47-1.72 (4H, m), 1.83-1.97 (1H, m), 4.19-4.26 (1H, m),4.45-4.53 (1H, m), 5.08-5.17 (3H, m), 6.46 (1H, br-s), 7.29-7.39 (5H,m), 9.57 (1H, s)

REFERENCE EXAMPLE 150N—[N-(4-Morpholinylcarbonyl)-L-leucyl]-L-norleucinal

473 mg (1.4 mmol) ofN—[N-(4-morpholinylcarbonyl)-L-leucyl]-L-norleucinol was used instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 315 mg (67%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 0.96 (3H, d, J=6 Hz), 0.97 (3H,d, J=6 Hz), 1.23-1.39 (4H, m), 1.50-1.76 (4H, m), 1.85-1.96 (1H, m),3.32-3.43 (4H, m), 3.63-3.72 (4H, m), 4.37-4.46 (2H, m), 4.86 (1H, d,J=8 Hz), 6.69 (1H, d, J=7 Hz), 9.56 (1H, s)

REFERENCE EXAMPLE 151 N—[N-(2-Furanylcarbonyl)-L-leucyl]-L-valinal

256 mg (0.8 mmol) of N—[N-(2-furanylcarbonyl)-L-leucyl]-L-valinol wasused instead ofN-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol inthe process according to Reference Example 144 to obtain 175 mg (72%) ofthe title compound.

1H-NMR (CDCl₃, δ): 0.90-1.02 (12H, m), 1.64-1.82 (3H, m), 2.29-2.36 (1H,m), 4.52 (1H, dd, J=8 Hz, 5 Hz), 4.67 (1H, td, J=8 Hz, 6 Hz), 6.51 (1H,dd, J=4 Hz, 2 Hz), 6.67-6.73 (2H, m), 7.14 (1H, dd, J=4 Hz, 1 Hz), 7.46(1H, dd, J=2 Hz, 1 Hz), 9.65 (1H, s)

REFERENCE EXAMPLE 1521-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethylester

Under ice-cooling, 5.9 g (31 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g(28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. Afterthe mixture was stirred at room temperature overnight, the reactionsolvent was distilled off under reduced pressure. Water was added to theresidue and the mixture was extracted with ethyl acetate twice. Theobtained organic layer was washed with a 10% aqueous potassiumhydrogensulfate solution, a saturated aqueous sodium hydrogencarbonatesolution and then saturated brine, it was dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, diethylether was added to the obtained residue, and the mixture was stirredovernight. The crystal was collected by filtration and heated and driedunder reduced pressure to obtain 10 g (91%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.78 (6H, m), 1.93-2.05 (2H, m), 2.12-2.25 (2H,m), 5.18 (2H, s), 6.24 (1H, s), 7.20-7.38 (5H, m), 7.38-7.51 (2H, m),7.77 (1H, s), 7.80-7.91 (2H, m)

REFERENCE EXAMPLE 1531-[(2-Benzothienylcarbonyl)amino]cyclohexanecarboxylic acid

42 ml of 2N aqueous sodium hydroxide solution was added to a solution of10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylicacid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture washeated under reflux for 3 days. After ether was added to the reactionsolution to wash it, the aqueous layer was neutralized by concentratedhydrochloric acid and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain 6.1 g (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.85 (6H, m), 1.91-2.08 (2H, m), 2.21-2.35, (2H,m), 6.22 (1H, s), 7.38-7.53 (2H, m), 7.80-7.93 (3H, m)

EXAMPLE 46 2-(2-Benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.1 g (21 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 5 g (16 mmol) of1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid in 50 ml ofmethylene chloride. After the mixture was stirred at room temperaturefor 4 hours, the reaction solution was concentrated under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine. The organic layer was dried with anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure toobtain 3.5 g (75%) of the title compound.

1H-NMR (CDCl₃, δ): 1.45-1.98 (10H, m), 7.38-7.51 (2H, m), 7.80-7.91 (2H,m), 7.93 (1H, s)

REFERENCE EXAMPLE 1541-[[[4-(Chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester

Under ice-cooling, 9.96 g (52 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 8.8 g (52 mmol) of 4-(chloromethyl)benzoic acid, 10 g (52mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride,15 g (152 mmol) of triethylamine and 8.63 g (56 mmol) of1-hydroxybenzotriazole in methylene chloride. After the mixture wasstirred at room temperature overnight, the reaction solvent wasdistilled off under reduced pressure. Water was added to the residue andthe mixture was extracted with ethyl acetate twice. The obtained organiclayer was washed with a 10% aqueous potassium hydrogensulfate solution,a saturated aqueous sodium hydrogencarbonate solution and then saturatedbrine and it was dried with anhydrous sodium sulfate. The obtainedresidue was purified by silica gel column chromatography to obtain 8.5 g(53%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.73 (6H, m), 1.83-2.00 (2H, m), 2.08-2.21 (2H,m), 3.71 (3H, s), 5.56 (2H, s), 6.30 (1H, s), 7.44 (2H, dd, J=8 Hz, 2Hz), 7.75 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 1551-[[[4-(Hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester

Under ice-cooling, 6.94 g (36 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g(35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After themixture was stirred at room temperature overnight, the reaction solventwas distilled off under reduced pressure. Water was added to the residueand the mixture was extracted with ethyl acetate twice. The obtainedorganic layer was washed with a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogencarbonate solution and thensaturated brine, it was dried with anhydrous sodium sulfate. Theobtained residue was purified by silica gel column chromatography toobtain 6.83 g (56%) of the title compound.

1H-NMR (CDCl₃, δ): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m), 4.73 (2H, m),5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m),7.62-7.79 (2H, m)

REFERENCE EXAMPLE 1561-[[[4-(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

30 ml of 40% aqueous dimethylamine solution was added to 4.5 g (14.5mmol) of1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester, and the mixture was heated under reflux for 3 hours. Thereaction solution was distilled off under reduced pressure, a saturatedaqueous sodium bicarbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, diisopropyl ether was added to theresidue, and the mixture was stirred overnight. The precipitated solidwas collected by filtration to obtain 2.3 g (50%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-2.19 (10H, m), 2.24 (6H, s), 3.46 (2H, s), 3.76(3H, s), 6.22 (1H, s), 7.38 (2H, d, J=9 Hz), 7.73 (2H, d, J=9 Hz)

REFERENCE EXAMPLE 1571-[[[4-(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 1 g (9 mmol) of methanesulfonyl chloride was addeddropwise to a solution of 3 g (8 mmol) of1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 2.46 g (24 mmol) of triethylamine in methylenechloride. After the mixture was stirred at room temperature for 1 hour,20 ml of 2N-dimethylamine-tetrahydrofuran solution was added thereto,and the mixture was stirred overnight. The reaction solution wasdistilled off under reduced pressure, a saturated aqueous sodiumbicarbonate solution was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure and it was purified by silica gel columnchromatography to obtain 700 mg (22%) of the title compound.

1H-NMR (CDCl₃, δ): 1.30-2.01 (9H, m), 2.12-2.28 (1H, m), 2.24 (6H, s),3.46 (2H, s), 5.17 (2H, s), 6.25 (1H, s), 7.21-7.32 (5H, m), 7.37 (2H,dd, J=9 Hz, 2 Hz), 7.10 (2H, dd, J=9 Hz, 2 Hz)

EXAMPLE 472-[4-[(Dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

29 ml of 2N aqueous sodium hydroxide solution was added to a solution of1.85 g (5.8 mmol) of1-[[[4-(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 29 ml of tetrahydrofuran, and the mixture washeated under reflux overnight. After the reaction mixture wasneutralized by concentrated hydrochloric acid, the reaction solution wasdistilled off under reduced pressure. 30 ml of methylene chloride, 1.76g (17 mmol) of triethylamine and 1.67 g (8.7 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate.

The solvent was distilled off under reduced pressure to obtain 1.33 g(80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.88 (10H, m), 2.25 (6H, s), 3.48 (2H, s), 7.43(2H, dd, J=9 Hz, 2 Hz), 7.96 (2H, dd, J=9 Hz, 2 Hz)

EXAMPLE 482-[4-[(Dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

0.7 ml of 2N aqueous sodium hydroxide solution was added to a solutionof 100 mg (0.25 mmol) of1-[[[4-(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 1 ml of tetrahydrofuran, and the mixture washeated under reflux overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction solution was distilled offunder reduced pressure. 3 ml of methylene chloride, 126 mg (1.25 mmol)of triethylamine and 96 mg (0.5 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 52 mg (68%) of the title compound.

1H-NMR (CDCl₃, δ): 1.50-1.88 (10H, m), 2.25 (6H, s), 3.48 (2H, s), 7.43(2H, dd, J=9 Hz, 2 Hz), 7.96 (2H, dd, J=9 Hz, 2 Hz)

REFERENCE EXAMPLE 1581-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 628 mg (5.5 mmol) of methanesulfonyl chloride wasadded dropwise to a solution of 1.83 g (5 mmol) of1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidphenylmethyl ester and 1.52 g (15 mmol) of triethylamine in methylenechloride. After the mixture was stirred at room temperature for 1 hour,5 ml of morpholine was added thereto and the mixture was stirredovernight. The reaction solution was distilled off under reducedpressure, a saturated aqueous sodium bicarbonate solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography to obtain 1 g(57%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.79 (6H, m), 1.89-2.03 (2H, m), 2.15-2.29 (2H,m), 2.43 (4H, t, J=5 Hz), 3.53 (2H, s), 3.70 (4H, t, J=5 Hz), 5.17 (2H,s), 6.21 (1H, s), 7.21-7.38 (5H, m), 7.39 (2H, d, J=8 Hz), 7.71 (2H, d,J=8 Hz)

REFERENCE EXAMPLE 1591-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

30 ml of morpholine was added to 4 g (13 mmol) of1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acidmethyl ester, and the mixture was heated under reflux for 1 hour. Thereaction solution was distilled off under reduced pressure, a saturatedaqueous sodium bicarbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, diethyl ether was added to theresidue, and the mixture was stirred overnight. The precipitated solidwas collected by filtration to obtain 3.8 g (83%) of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.80 (6H, m), 1.80-1.99 (2H, m), 2.11-2.21 (2H,m), 2.38-2.49 (4H, m), 3.54 (2H, s), 3.63-3.74 (4H, m), 3.73 (3H, s),6.22 (1H, s), 7.41 (2H, d, J=8 Hz), 7.73 (2H, d, J=8 Hz)

EXAMPLE 492-[4-(4-Morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

18 ml of 2N aqueous sodium hydroxide solution was added to a solution of2.07 g (5.7 mmol) of1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester in 18 ml of tetrahydrofuran, and the mixture washeated under reflux overnight. After the mixture was neutralized byconcentrated hydrochloric acid, the reaction solution was distilled offunder reduced pressure. 30 ml of methylene chloride, 1.74 g (17 mmol) oftriethylamine and 1.65 g (8.6 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 1.27 g (60%) of the title compound.

1H-NMR (CDCl₃, δ): 1.42-1.80 (10H, m), 2.44 (4H, t, J=5 Hz) 3.56 (2H,s), 3.71 (4H, t, J=5 Hz), 7.45 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

EXAMPLE 502-[4-(4-Morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

2 ml of 2N aqueous sodium hydroxide solution was added to a solution of300 mg (0.69 mmol) of1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 2 ml of tetrahydrofuran, and the mixture washeated under reflux overnight. After the reaction mixture wasneutralized by concentrated hydrochloric acid, the reaction solution wasdistilled off under reduced pressure. 3 ml of methylene chloride, 698 mg(6.9 mmol) of triethylamine and 264 mg (1.38 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedto the residue, and the mixture was stirred for 1 hour. The reactionsolution was distilled off under reduced pressure, a saturated aqueoussodium bicarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 191 mg (80%) of the title compound.

1H-NMR (CDCl₃, δ): 1.42-1.80 (10H, m), 2.44 (4H, t, J=5 Hz), 3.56 (2H,s), 3.71 (4H, t, J=5 Hz), 7.45 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1601-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester

Under ice-cooling, 5.29 g (374 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added toa solution of 8.84 g (23.0 mmol) of4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide,4.19 g (27.6 mmol) of 1-hydroxybenzotriazole, 6.44 g (27.6 mmol) of1-aminocyclohexanecarboxylic acid phenylmethyl ester and 11.9 g (92mmol) of N,N-diisopropylethylamine in 120 ml of dimethylformamide. Afterthe mixture was stirred at room temperature overnight, the reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded thereto, and the mixture was successively washed with water, asaturated aqueous sodium hydrogencarbonate solution and saturated brine,followed by drying with anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, ether was added to the residue,and the crystal was washed to obtain 11.8 g (quantitative) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.30-1.42 (1H, m), 1.45-1.61 (2H, m), 1.62-1.75 (3H,m), 1.91-2.01 (2H, m), 2.18-2.24 (2H, m), 2.37 (3H, s), 2.56 (4H, t, J=5Hz), 3.59 (4H, t, J=5 Hz), 5.18 (2H, s), 6.23 (1H, br-s), 6.88 (1H, s),7.25-7.34 (5H, m), 7.76 (2H, dd, J=8 Hz, 2 Hz), 7.90 (2H, dd, J=8 Hz, 2Hz)

REFERENCE EXAMPLE 1611-[([4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid

35 ml of 2N aqueous sodium hydroxide solution was added to a solution of11.8 g (23.0 mmol) of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in 120 ml of tetrahydrofuran, and the mixturewas heated under reflux for 15 hours. Ether was added to the reactionsolution and the aqueous layer was separated. Concentrated hydrochloricacid was added to the separated aqueous layer to neutralize it, and theprecipitated crystal was collected by filtration to obtain 6.60 g (67%)of the title compound.

1H-NMR (CDCl₃, δ): 1.28-1.38 (1H, m), 1.40-1.51 (2H, m), 1.58-1.73 (3H,m), 1.85-2.00 (2H, m), 2.10-2.21 (2H, m), 2.47 (3H, s), 2.66-2.75 (4H,m), 3.54-4.04 (4H, m), 6.38 (1H, br-s), 6.83 (1H, s), 7.69 (2H, d, J=8Hz), 7.76 (2H, d, J=8 Hz)

EXAMPLE 512-[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

450 mg (2.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added to a solution of 910 mg (2.1 mmol) of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid in 20 ml of dimethylformamide. After the mixture was stirred atroom temperature for 4 hours, the reaction solution was concentratedunder reduced pressure, ethyl acetate was added thereto, and the mixturewas successively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain 577 mg (67%) of the title compound.

1H-NMR (CDCl₃, δ): 1.51-1.62 (1H, m), 1.62-1.71 (1H, m), 1.71-1.78 (2H,m), 1.78-1.90 (6H, m), 2.37 (3H, s), 2.56 (4H, t, J=5 Hz), 3.60 (4H, t,J=5 Hz), 6.92 (1H, s), 7.94 (2H, d, J=8 Hz), 8.00 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 1624-[[2-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acidhydrobromide

After a solution of 2.47 g (16.9 mmol) of4-(4-morpholinyl)piperidine-1-thiocarboxamide and 4.08 g (16.9 mmol) of4-(bromoacetyl)benzoic acid in 150 ml of ethanol was heated under refluxfor 2 hours, the mixture was left to be cooled to room temperature.After 150 ml of ether was added to the reaction solution and the mixturewas stirred at 4° C. overnight, the precipitated crystal was collectedby filtration to obtain 4.64 g (95%) of the title compound.

1H-NMR (DMSO-d₆, δ): 1.68-1.80 (2H, m), 2.17-2.25 (2H, m), 3.07-3.20(4H, m), 3.21-3.63 (5H, m), 3.64-3.78 (1H, m), 3.98-4.10 (1H, m),4.10-4.18 (2H, m), 7.51 (1H, s), 7.95-7.99 (4H, m)

REFERENCE EXAMPLE 1631-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester

4.50 g (9.90 mmol) of4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acidhydrobromide was used instead of4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide and1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester wasused instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester inthe process according to Reference Example 160 to obtain 5.08 g(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.42 (1H, m), 1.45-1.74 (7H, m), 1.93-2.01 (4H,m), 2.14-2.21 (2H, m), 2.41-2.50 (1H, m), 2.58 (4H, t, J=5 Hz), 3.07(2H, dd, J=13 Hz, 13 Hz), 3.73 (4H, t, J=5 Hz), 3.74 (3H, s), 4.13 (2H,d, J=13 Hz), 6.25 (1H, br-s), 6.86 (1H, s), 7.78 (2H, dd, J=8 Hz, 2 Hz),7.90 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 1641-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid

5.08 g (9.90 mmol) of1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid methyl ester was used instead of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid phenylmethyl ester in the process according to Reference Example161 to obtain 4.93 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.45 (1H, m), 1.46-1.60 (2H, m), 1.61-1.77 (5H,m), 1.90-2.03 (4H, m), 2.15-2.25 (2H, m), 2.44-2.52 (1H, m), 2.62 (4H,t, J=5 Hz), 3.08 (2H, dd, J=13 Hz, 13 Hz), 3.78 (4H, t, J=5 Hz), 4.14(2H, d, J=13 Hz), 6.70 (1H, br-s), 6.88 (1H, s), 7.79 (2H, d, J=8 Hz),7.90 (2H, d, J=8 Hz)

EXAMPLE 522-[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one

4.93 g (9.90 mmol) of1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid was used instead of1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexanecarboxylicacid in the process according to Example 51 to obtain 3.00 g (63%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.50-1.61 (1H, m), 1.61-1.71 (3H, m), 1.71-1.79 (2H,m), 1.79-1.89 (5H, m), 1.91-2.00 (2H, m), 2.40-2.48 (1H, m), 2.59 (4H,t, J=5 Hz), 3.09 (2H, d, J=12 Hz), 3.74 (4H, t, J=5 Hz), 4.13 (2H, d,J=12 Hz), 6.90 (1H, s), 7.96 (2H, dd, J=7 Hz, 2 Hz), 8.00 (2H, dd, J=7Hz, 2 Hz)

REFERENCE EXAMPLE 165N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinol

288 mg (2 mmol) of L-phenylglycinol was added to a solution of 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added, and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain 730 mg (98%) of the title compound.

1H-NMR (CDCl₃, δ): 1.29-1.80 (6H, m), 1.91-2.12 (2H, m), 2.19-2.38 (2H,m), 2.91 (1H, br-s), 3.73-3.83 (1H, m), 3.89-4.02 (1H, m), 5.07-5.20(1H, m), 6.26 (1H, s), 7.20-7.49 (8H, m), 7.83 (1H, s), 7.84-7.92 (2H,m)

REFERENCE EXAMPLE 166N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under ice-cooling, 585 mg (1.38 mmol) of Des Martin periodinane wasadded to a solution of 100 mg (0.23 mmol) ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added to the reaction solution.Sodium thiosulfate was added thereto until the solution becametransparent, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and saturated brine and dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and ethyl acetatewas added to the obtained residue, and the mixture was stirred for 1hour. The precipitated solid was collected by filtration to obtain 55 mg(57%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-1.80 (6H, m), 1.83-2.18 (2H, m), 2.23-2.40 (2H,m), 5.51 (1H, d, J=5 Hz), 6.10 (1H, s), 7.21-7.52 (7H, m), 7.83 (1H, s),7.84-7.96 (2H, m), 8.18 (1H, d, J=5 Hz), 9.55 (1H, s)

REFERENCE EXAMPLE 167N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninol

284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added, and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain 722 mg (98%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-2.29 (16H, m), 2.45-2.63 (1H, m), 3.06 (1H,br-s), 3.45-3.61 (1H, m), 3.73-3.82 (1H, m), 3.97-4.05 (1H, m), 6.29(1H, s), 6.85 (1H, br-s), 7.38-7.50 (2H, m), 7.82 (1H, s), 7.83-7.90(2H, m)

REFERENCE EXAMPLE 168N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninal

Under an argon gas atmosphere, 245 mg (1.9 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 297 mg(1.9 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, 100 mg (0.23 mmol) ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninolwas added to the reaction solution, and the mixture was stirred at thesame temperature for 2 hours. The reaction solution was poured toice-water, and the mixture was extracted with ethyl acetate twice. Theorganic layer was washed with a 10% aqueous citric acid solution, asaturated aqueous sodium hydrogencarbonate solution and then saturatedbrine, and after it was dried with anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. 20 ml of diisopropylether was added to the residue, and the mixture was stirred at roomtemperature for 18 hours. The obtained crystal was collected byfiltration to quantitatively obtain the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.80 (9H, m), 1.91-2.09 (5H, m), 2.20-2.35 (2H,m), 2.50-2.63 (1H, m), 4.43-4.59 (1H, m), 6.19 (1H, s), 7.38-7.52 (2H,m), 7.67 (1H, d, J=7 Hz), 7.71 (1H, s), 7.80-7.89 (2H, m), 9.61 (1H, s)

REFERENCE EXAMPLE 169N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

44 mg (0.32 mmol) of L-phenylglycinol was added to a solution of 100 mg(0.29 mmol) of2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added, and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain 46 mg (34%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.80 (6H, m), 1.92-2.10 (2H, m), 2.18-2.32 (2H,m), 2.37-2.50 (4H, m), 2.99 (1H, br-s), 3.55 (2H, s), 3.62-3.71 (4H, m),3.71-3.83 (1H, m), 3.91-4.02 (1H, m), 5.05-5.18 (1H, m), 6.24 (1H, s),7.17-7.37 (6H, m), 7.44 (2H, d, J=8 Hz), 7.73 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 170N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under ice-cooling, 254 mg (0.6 mmol) of Des Martin periodinane was addedto a solution of 46 mg (0.1 mmol) ofN-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added to the reaction solution.Sodium thiosulfate was added thereto until the solution becametransparent, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and then saturated brine, and dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, ethylacetate was added to the obtained residue, and the mixture was stirredfor 1 hour. The precipitated solid was collected by filtration to obtain30 mg (60%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.37 (10H, m), 2.37-2.60 (4H, m), 3.55 (2H, s),3.61-3.80 (4H, m), 5.49 (1H, d, J=6 Hz), 6.16 (1H, s), 7.20-7.58 (7H,m), 7.75 (2H, d, J=8 Hz), 8.27 (1H, d, J=6 Hz), 9.54 (1H, s)

REFERENCE EXAMPLE 171N-[[1-[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

43 mg (0.32 mmol) of L-methioninol was added to a solution of 100 mg(0.29 mmol) of2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in3 ml of N,N-dimethylformamide, and the mixture was stirred overnight.Water was slowly added, and the precipitated crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain 65 mg (49%) of the title compound.

1H-NMR (CDCl₃, δ): 1.31-2.23 (15H, m), 2.35-2.45 (4H, m), 2.45-2.62 (2H,m), 3.12 (1H, br-s), 3.40-3.60 (3H, m), 3.60-3.82 (5H, m), 3.95-4.05(1H, m), 6.28 (1H, s), 6.80 (1H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 7.72(2H, d, J=8 Hz)

REFERENCE EXAMPLE 172N-[[1-[[[4-(4-Morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

Under ice-cooling, 356 mg (0.84 mmol) of Des Martin periodinane wasadded to a solution of 65 mg (0.14 mmol) ofN-[[1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin 5 ml of methylene chloride, and the mixture was stirred for 1 hour.At the same temperature, 10 ml of ethyl acetate and 10 ml of a saturatedaqueous sodium bicarbonate solution were added to the reaction solution.Sodium thiosulfate was added thereto until the solution becametransparent, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution and saturated brine, and dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to obtain 55 mg(85%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.80 (21H, m), 3.56 (2H, s), 3.60-3.81 (4H, m),4.40-4.58 (1H, m), 5.12 (1H, d, J=7 Hz), 6.18 (1H, s), 7.44 (2H, d, J=8Hz), 7.73 (2H, d, J=8 Hz), 9.59 (1H, s)

REFERENCE EXAMPLE 173N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

100 mg (0.74 mmol) of L-methioninol was added to a solution of 250 mg(0.68 mmol) of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 20 ml of dimethylformamide. After the mixture was stirred at 80° C.for 15 hours, the reaction solution was concentrated under reducedpressure, ethyl acetate was added thereto, and the mixture wassuccessively washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, followed by drying withanhydrous sodium sulfate. After the solvent was distilled off underreduced pressure, diisopropyl ether was added to the residue to wash thecrystal to obtain 319 mg (86%) of the title compound.

1H-NMR (CDCl₃, δ): 1.37-1.61 (3H, m), 1.65-1.80 (3H, m), 1.80-1.86 (2H,m), 1.96-2.05 (2H, m), 2.07 (3H, s), 2.15-2.29 (2H, m), 2.37 (3H, s),2.51-2.60 (2H, m), 2.56 (4H, t, J=5 Hz), 3.14-3.21 (1H, m), 3.50-3.56(1H, m), 3.59 (4H, t, J=5 Hz), 3.77-3.84 (1H, m), 4.00-4.06 (1H, m),6.30 (1H, br-s), 6.85 (1H, d, J=7 Hz), 6.90 (1H, s), 7.76 (2H, dd, J=8Hz, 2 Hz), 7.92 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 174N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

Under an argon gas atmosphere, 453 mg (3.5 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 658 mg(3.5 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, a solution of 319 mg (0.58 mmol) ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin 3 ml of anhydrous dimethyl sulfoxide was added to the reactionsolution, and the mixture was stirred at the same temperature for 2hours. The reaction solution was poured to ice-water, and the mixturewas extracted with ethyl acetate twice. After the organic layer waswashed with a saturated aqueous sodium hydrogencarbonate solution andthen saturated brine and dried with anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. 20 ml of diisopropylether was added to the residue, and the mixture was stirred at roomtemperature for 18 hours. The obtained crystal was collected byfiltration to obtain 203 mg (64%) of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.78 (6H, m), 1.98-2.08 (3H, m), 2.02 (3H, s),2.21-2.57 (3H, m), 2.38 (3H, s), 2.55 (4H, t, J=5 Hz), 2.56 (2H, m),3.61 (4H, t, J=5 Hz), 4.49 (1H, dt, J=8 Hz, 5 Hz), 6.17 (1H, br-s), 6.90(1H, s), 7.78 (2H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 7.92 (2H, d, J=8Hz), 9.62 (1H, s)

REFERENCE EXAMPLE 175N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

96 mg (0.7 mmol) of L-phenylglycinol was used instead of L-methioninolin the process according to Reference Example 173 to obtain 220 mg (57%)of the title compound.

1H-NMR (CDCl₃, δ): 1.34-1.43 (1H, m), 1.42-1.61 (2H, m), 1.61-1.79 (3H,m), 1.96-2.10 (2H, m), 2.20-2.29 (1H, m), 2.30-2.36 (1H, m), 2.37 (3H,s), 2.56 (4H, t, J=5 Hz), 3.01-3.08 (1H, m), 3.60 (4H, t, J=5 Hz),3.76-3.85 (1H, m), 3.92-4.01 (1H, m), 5.09-5.15 (1H, m), 6.27 (1H,br-s), 6.90 (1H, s), 7.24-7.30 (3H, m), 7.31-7.36 (2H, m), 7.37 (1H, d,J=7 Hz), 7.78 (2H, d, J=8 Hz), 7.92 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 176N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

Under an argon gas atmosphere, 310 mg (2.4 mmol) ofN,N-diisopropylethylamine was added dropwise to a solution of 382 mg(2.4 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrousdimethyl sulfoxide and 5 ml of anhydrous methylene chloride underice-cooling, and the mixture was stirred for 15 minutes. Further, underice-cooling, a solution of 220 mg (0.4 mmol) ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolin 3 ml of anhydrous dimethyl sulfoxide was added to the reactionsolution, and the mixture was stirred at the same temperature for 30minutes. After the completion of the reaction, 200 ml of water was addedto the reaction solution under ice-cooling, and thereafter, the mixturewas stirred at room temperature for 3 hours. The precipitated crystalwas washed with diethyl ether again to obtain 67 mg (31%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.35-1.82 (6H, m), 2.25-2.39 (2H, m), 2.50-2.59 (1H,m), 2.62 (3H, s), 2.75 (4H, t, J=5 Hz), 3.06-3.15 (1H, m), 3.72 (4H, t,J=5 Hz), 5.51 (1H, d, J=6 Hz), 6.16 (1H, br-s), 6.91 (1H, s), 7.21-7.38(5H, m), 7.38 (1H, d, J=6 Hz), 7.79 (2H, d, J=8 Hz), 7.92 (2H, d, J=8Hz), 9.56 (1H, s)

REFERENCE EXAMPLE 177N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninol

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein the process according to Reference Example 173 to obtain 501 mg (81%)of the title compound.

1H-NMR (CDCl₃, δ): 1.35-1.80 (7H, m), 1.81-1.89 (2H, m), 1.92-2.09 (4H,m), 2.07 (3H, s), 2.15-2.23 (3H, m), 2.41-2.49 (1H, m), 2.54 (2H, t, J=6Hz), 2.57 (4H, t, J=5 Hz), 3.08 (2H, dd, J=13 Hz, 13 Hz), 3.18 (1H, t,J=7 Hz), 3.50-3.58 (1H, m), 3.74 (4H, t, J=5 Hz), 3.77-3.85 (1H, m),4.00-4.08 (1H, m), 4.12 (2H, d, J=13 Hz), 6.30 (1H, br-s), 6.83 (1H, d,J=8 Hz), 6.88 (1H, s), 7.77 (2H, d, J=8 Hz), 7.96 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 178N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninal

501 mg (0.81 mmol) ofN-[[1-[[[4-[2-[(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolwas used instead ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Reference Example 174 to obtain 100 mg (20%)of the title compound.

1H-NMR (CDCl₃, δ): 1.36-1.56 (3H, m), 1.61-1.79 (6H, m), 1.93-2.07 (5H,m), 2.02 (3H, s), 2.04-2.15 (2H, m), 2.40 (2.49 (1H, m), 2.45 (2H, t,J=6 Hz), 2.58 (4H, t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.74 (4H,t, J=5 Hz), 4.12 (2H, d, J=12 Hz), 4.49 (1H, dd, J=8 Hz, 5 Hz), 6.15(1H, br-s), 6.88 (1H, s), 7.78 (2H, d J=8 Hz), 7.85 (1H, d, J=8 Hz),7.93 (2H, d, J=8 Hz), 9.62 (1H, s)

REFERENCE EXAMPLE 179N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinol

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 137 mg (1.00 mmol) of L-phenylglycinol was used instead ofL-methioninol in the process according to Reference Example 173 toobtain 324 mg (52%) of the title compound.

1H-NMR (CDCl₃, δ): 1.32-1.78 (9H, m), 1.95-2.11 (4H, m), 2.20-2.27 (1H,m), 2.29-2.36 (1H, m), 2.40-2.49 (1H, m) 2.59 (4H, t, J=5 Hz), 3.09 (2H,dd, J=13 Hz, 13 Hz), 3.74 (4H, t, J=5 Hz), 3.78-3.82 (1H, m), 3.96-4.00(1H, m), 4.12 (2H, d, J=13 Hz), 5.09-5.14 (1H, m), 6.28 (1H, br-s), 6.88(1H, s), 7.25-7.30 (1H, m) 7.30-7.35 (4H, m), 7.78 (1H, d, J=8 Hz), 7.78(2H, dd, J=7 Hz, 2 Hz), 7.92 (2H, dd, J=7 Hz, 2 Hz)

REFERENCE EXAMPLE 180N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinal

324 mg (0.52 mmol) ofN-[[1-[[[4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinolwas used instead ofN-[[1-[[[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninolin the process according to Reference Example 174 to obtain 128 mg (40%)of the title compound.

1H-NMR (CDCl₃, δ): 1.30-1.85 (8H, m), 1.92-2.13 (4H, m), 2.25-2.50 (3H,m), 2.59 (4H, t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.74 (4H, t,J=5 Hz), 4.13 (2H, d, J=12 Hz), 5.51 (1H, d, J=6 Hz), 6.14 (1H, br-s),6.88 (1H, s), 7.30-7.41 (5H, m), 7.79 (2H, d, J=8 Hz), 7.93 (2H, d, J=8Hz), 8.34 (1H, d, J=6 Hz), 9.56 (1H, s)

REFERENCE EXAMPLE 181N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of423 mg (2 mmol) of L-phenylglycine methyl ester hydrochloride and 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in10 ml of toluene, and the mixture was heated under reflux overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with a 10% aqueouspotassium hydrogensulfate solution and saturated brine, followed bydrying with anhydrous sodium sulfate. After the solvent was distilledoff under reduced pressure, diethyl ether was added thereto, and themixture was stirred overnight. The precipitated solid was collected byfiltration and dried under reduced pressure to obtain 670 mg (91%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.25-1.80 (6H, m), 1.90-2.08 (2H, m), 2.23-2.40 (2H,m), 3.69 (3H, s), 5.53 (1H, d, J=7 Hz), 6.10 (1H, s), 7.23-7.49 (7H, m),7.81 (1H, s), 7.83-7.91 (2H, m), 8.13 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 182N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of419 mg (2 mmol) of L-methionine methyl ester hydrochloride and 500 mg(1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in10 ml of toluene, and the mixture was heated under reflux overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with a 10% aqueouspotassium hydrogensulfate solution and saturated brine, followed bydrying with anhydrous sodium sulfate. After the solvent was distilledoff under reduced pressure, diethyl ether was added thereto, and themixture was stirred overnight. The precipitated solid was collected byfiltration and dried under reduced pressure to obtain 678 mg (86%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.30-1.81 (8H, m), 1.95-2.09 (5H, m), 2.11-2.39 (2H,m), 2.43-2.61 (2H, m), 3.71 (3H, s), 4.61-4.73 (1H, m), 6.16 (1H, s),7.38-7.45 (2H, m), 7.59 (1H, d, J=8 Hz), 7.80 (1H, s), 7.82-7.90 (2H, m)

REFERENCE EXAMPLE 183N-[[1-[[[4-(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 85mg (0.42 mmol) of L-phenylglycine methyl ester hydrochloride and 100 mg(0.35 mmol) of2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 3 ml of toluene, and the mixture was heated under reflux overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with saturatedbrine and dried with anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, diethyl ether was added thereto,and the mixture was stirred overnight. The precipitated solid wascollected by filtration and dried under reduced pressure to obtain 62 mg(39%) of the title compound.

1H-NMR (CDCl₃, δ): 1.27-1.80 (7H, m), 1.83-2.09 (2H, m), 2.18-2.39 (1H,m), 2.25 (6H, s), 3.47 (2H, s), 3.69 (3H, s), 5.53 (1H, d, J=7 Hz), 6.07(1H, s), 7.10-7.25 (7H, m), 7.73 (2H, d, J=8 Hz), 8.28 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 184N-[[1-[[[4-(Dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

129 mg (1 mmol) of diisopropylethylamine was added to a suspension of 84mg (0.42 mmol) of L-methionine methyl ester hydrochloride and 100 mg(0.35 mmol) of2-[4-[(dimethylamino)methyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein 3 ml of toluene, and the mixture was heated under reflux overnight.After the solvent was distilled off under reduced pressure, ethylacetate was added thereto, and the mixture was washed with saturatedbrine and dried with sodium sulfate. After the solvent was distilled offunder reduced pressure, diethyl ether was added thereto, and the mixturewas stirred overnight. The precipitated solid was collected byfiltration and dried under reduced pressure to obtain 93 mg (59%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.29-1.58 (4H, m), 1.58-1.79 (4H, m), 1.92-2.35 (7H,m), 2.25 (6H, s), 2.43-2.59 (2H, m), 3.47 (2H, s), 3.71 (3H, s),4.61-4.72 (1H, m), 6.10 (1H, s), 7.41 (2H, d, J=8 Hz), 7.69 (1H, d, J=8Hz), 7.73 (2H, d, J=8 Hz)

REFERENCE EXAMPLE 185N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was addedto a solution of 411 mg (1.00 mmol) of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml ofdimethylformamide. After the mixture was stirred at 80° C. for 15 hours,the reaction solution was concentrated under reduced pressure, ethylacetate was added thereto, and the mixture was successively washed withwater, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine, followed by drying with anhydrous sodium sulfate. Afterthe solvent was distilled off under reduced pressure, the residue waspurified by silica gel chromatography to obtain 191 mg (33%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.33-1.60 (3H, m), 1.63-1.78 (3H, m), 1.97-2.05 (3H,m), 2.05 (3H, s), 2.15-2.35 (3H, m), 2.37 (3H, s), 2.50-2.58 (2H, m),2.56 (4H, t, J=5 Hz), 3.59 (4H, t, J=5 Hz), 3.71 (3H, s), 4.69 (1H, dt,J=7 Hz, 5 Hz), 6.13 (1H, br-s), 6.90 (1H, s), 7.72 (1H, d, J=7 Hz), 7.78(2H, dd, J=8 Hz, 2 Hz), 7.92 (2H, dd, J=8 Hz, 2 Hz)

REFERENCE EXAMPLE 186N-[[1-[[[4-[2-(4-Methyl-1-piperazinyl)-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

202 mg (1.00 mmol) of L-phenylglycine methyl ester hydrochloride wasused instead of L-methionine methyl ester hydrochloride in the processaccording to Reference Example 185 to obtain 156 mg (24%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.25-1.41 (1H, m), 1.41-1.55 (2H, m), 1.60-1.76 (3H,m), 1.94-2.05 (2H, m), 2.25-2.40 (2H, m), 2.37 (3H, s), 2.56 (4H, t, J=5Hz), 3.59 (4H, t, J=5 Hz), 3.69 (3H, s), 5.54 (1H, d, J=7 Hz), 6.08 (1H,br-s), 6.89 (1H, s), 7.26-7.35 (3H, m), 7.38-7.41 (2H, m), 7.78 (2H, d,J=8 Hz), 7.92 (2H, d, J=8 Hz), 8.29 (1H, d, J=7 Hz)

REFERENCE EXAMPLE 187N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-methioninemethyl ester

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onein the process according to Reference Example 185 to obtain 439 mg (68%)of the title compound.

1H-NMR (CDCl₃, δ): 1.31-1.79 (8H, m), 1.92-2.05 (5H, m), 2.05 (3H, s),2.15-2.34 (3H, m), 2.40-2.49 (1H, m), 2.53 (2H, t, J=7 Hz), 2.59 (4H, t,J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.71 (3H, s), 3.74 (4H, t, J=5Hz), 4.13 (2H, d, J=12 Hz), 4.69 (1H, dt, J=8 Hz, 5 Hz), 6.12 (1H,br-s), 6.88 (1H, s), 7.72 (1H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz)

REFERENCE EXAMPLE 188N-[[1-[[[4-[2-[4-(4-Morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycinemethyl ester

481 mg (1.00 mmol) of2-[4-[2-[4-(4-morpholinyl)-1-piperidinyl]-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-onewas used instead of2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-oneand 202 mg (1.00 mmol) of L-phenylglycine methyl ester hydrochloride wasused instead of L-methionine methyl ester hydrochloride in the processaccording to Reference Example 185 to obtain 156 mg (24%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.30-1.41 (1H, m), 1.42-1.60 (3H, m), 1.61-1.77 (4H,m), 1.92-2.08 (4H, m), 2.25-2.37 (2H, m), 2.40-2.49 (1H, m), 2.59 (4H,t, J=5 Hz), 3.08 (2H, dd, J=12 Hz, 12 Hz), 3.69 (3H, s), 3.74 (4H, t,J=5 Hz), 4.12 (2H, d, J=12H), 5.54 (1H, d, J=7 Hz), 6.07 (1H, br-s),6.87 (1H, s), 7.26-7.36 (3H, m), 7.37-7.42 (2H, m), 7.77 (2H, d, J=8Hz), 7.91 (2H, d, J=8 Hz), 8.30 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 189N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 530 mg (3.5 mmol) ofL-phenylglycine and 500 mg (1.75 mmol) of2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 259 mg (34%) of the title compound.

1H-NMR (CDCl₃, δ): 1.25-1.80 (6H, m), 1.83-2.03 (2H, m), 2.12-2.40 (2H,m), 4.47 (1H, d, J=5 Hz), 6.11 (1H, s), 7.18-7.55 (8H, m), 7.79 (1H, s),7.80-7.91 (2H, m)

REFERENCE EXAMPLE 190N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 522 mg (3.5 mmol) ofL-methionine and 500 mg (1.75 mmol) of2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 170 mg (22%) of the title compound.

1H-NMR (CDCl₃, δ): 1.21-2.99 (17H, m), 4.51-4.68 (1H, m), 6.42 (1H, s),6.75-6.85 (1H, m), 7.32-7.50 (2H, m), 7.74-7.98 (3H, m)

REFERENCE EXAMPLE 191N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) ofL-phenylglycine and 500 mg (1.9 mmol) of2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to obtain 120 mg (17%) of the titlecompound.

1H-NMR (CDCl₃, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d,J=7 Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35(3H, m), 7.41 (2H, d, J=8 Hz), 7.83 (1H, d, J=7 Hz), 10.92 (1H, s)

REFERENCE EXAMPLE 192N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 575 mg (3.9 mmol) ofL-methionine and 500 mg (1.9 mmol) of2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 503 mg (72%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.33 (15H, m), 2.42-2.61 (2H, m), 4.58-4.72 (1H,m), 6.21 (1H, dd, J=5 Hz, 3 Hz), 6.28 (1H, s), 6.69 (1H, d, J=3 Hz),6.78 (1H, d, J=5 Hz), 7.29 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 193N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine

10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) ofL-phenylglycine and 500 mg (1.9 mmol) of2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium hydrogensulfate, and the solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography to obtain 92 mg (22%) ofthe title compound.

1H-NMR (CDCl₃, δ): 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H,m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6 Hz), 6.01 (1H, s),6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m)

REFERENCE EXAMPLE 194N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-methionine

10 ml of N-methylmorpholine was added to 298 mg (2 mmol) of L-methionineand 259 mg (1 mmol) of2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixturewas stirred and heated under reflux overnight. The reaction solution wasdistilled off under reduced pressure, a 10% aqueous potassiumhydrogensulfate solution was added thereto, and the mixture wasextracted with methylene chloride three times. The obtained organiclayer was dried with anhydrous sodium hydrogensulfate, and the solventwas distilled off under reduced pressure. Ethyl acetate was added to theobtained residue, and the mixture was stirred overnight. Theprecipitated solid was collected by filtration and dried under reducedpressure to obtain 52 mg (13%) of the title compound.

1H-NMR (CDCl₃, δ): 1.20-2.62 (17H, m), 3.86 (3H, s), 4.56-4.71 (1H, m),6.27 (1H, s), 6.95 (2H, d, J=9 Hz), 7.75 (2H, d, J=9 Hz), 7.86 (1H, d,J=8 Hz)

REFERENCE EXAMPLE 195N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-methionine

A solution of 491 mg (2 mmol) of2-[(E)-2-(2-furanyl)ethenyl]-3-oxo-1-azaspiro[4.5]dec-1-en-4-one and 597mg (4 mmol) of L-methionine in 20 ml of N-methylmorpholine was heatedunder reflux for 15 hours. After ethyl acetate and water were added tothe reaction solution, it was acidified using concentrated hydrochloricacid. The organic layer was separated and successively washed with waterand saturated brine, followed by drying with anhydrous sodium sulfate.After the solvent was distilled off under reduced pressure, the residuewas purified by silica gel chromatography to obtain 74 mg (9%) of thetitle compound.

1H-NMR (CDCl₃, δ): 1.24-1.48 (3H, m), 1.59-1.71 (3H, m), 1.87-1.98 (2H,m), 2.00-2.25 (4H, m), 2.05 (3H, s), 2.51-2.63 (2H, m), 4.63 (1H, dt,J=8 Hz, 5H), 6.00 (1H, br-s), 6.40 (1H, d, J=15 Hz), 6.46 (1H, dd, J=3Hz, 2 Hz), 6.59 (1H, d, J=3 Hz), 7.40 (1H, d, J=15 Hz), 7.45 (1H, d, J=2Hz), 7.76 (1H, d, J=8 Hz)

REFERENCE EXAMPLE 196N-[[1-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]L-valinol

2.00 g (7.48 mmol) of1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was usedinstead of 2-benzothiophenecarboxylic acid, and 772 mg (7.48 mmol) ofL-valinol was used instead of 1-aminocyclohexanecarboxylic acidphenylmethyl ester in the process according to Reference Example 152 toobtain 2.67 g (quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.90 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz) 1.29-1.46(3H, m), 1.56-1.72 (3H, m), 1.78-1.85 (1H, m), 1.88-1.96 (2H, m),1.96-2.06 (2H, m), 2.75-2.90 (1H, br-s), 3.48-3.55 (1H, m), 3.68-3.78(2H, m), 5.06 (1H, br-s), 5.00 (1H, d, J=13 Hz), 5.10 (1H, d, J=13 Hz),6.35 (1H, br-s), 6.37 (1H, dd, J=3 Hz, 2 Hz), 6.43 (1H, dd, J=3 Hz, 1Hz), 7.43 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 197N-[[1-[[(2-Furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

2.67 g ofN-[[1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin the process according to Reference Example 166 to obtain 2.08 g(83.7%, 2 steps) of the title compound.

1H-NMR (CDCl₃, δ): 0.92 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz), 1.26-1.46(3H, m), 1.52-1.70 (3H, m), 1.86-1.96 (2H, m), 1.96-2.04 (1H, m),2.05-2.14 (1H, m), 2.28-2.36 (1H, m), 4.46-4.52 (1H, m), 4.92-4.99 (1H,br-s), 5.04 (1H, d, J=13 Hz), 5.09 (1H, d, J=13 Hz), 6.36 (1H, dd, J=3Hz, 2 Hz), 6.41 (1H, d, J=3 Hz), 7.04-7.16 (1H, m), 7.42 (1H, d, J=2Hz), 9.61 (1H, s)

REFERENCE EXAMPLE 198N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinol

1.07 ml (6.12 mmol) of diisopropylethylamine was added to a solution of252 mg (2.45 mmol) of L-valinol and 500 mg (2.04 mmol) of2-[(E)-2-(2-furanyl)ethenyl]-3-oxo-1-azaspiro[4.5]dec-1-en-4-one in 15ml of toluene, and the mixture was stirred and heated under reflux for 4days. The reaction solution was distilled off under reduced pressure,and the residue was purified by silica gel chromatography to obtain 481mg (67.7%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz) 1.34-1.52(3H, m), 1.60-1.74 (3H, m), 1.80-1.88 (1H, m), 1.94-2.06 (2H, m),2.08-2.18 (2H, m), 3.16-3.21 (1H, m), 3.51-3.57 (1H, m), 3.68-3.78 (2H,m), 5.72 (1H, br-s), 6.35 (1H, d, 15 Hz), 6.47 (1H, dd, J=3 Hz, 2 Hz),6.58 (1H, dd, J=3 Hz, 1 Hz), 6.73 (1H, br-d, J=9 Hz), 7.41 (1H, d, J=15Hz), 7.46 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 199N-[[1-[[(E)-3-(2-Furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinal

481 mg (1.38 mmol) ofN-[[1-[[(E)-3-(2-furanyl)-1-oxo-2-propenyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin the process according to Reference Example 166 to obtain 449 mg(93.9%) of the title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz) 1.30-1.74(6H, m), 1.92-2.02 (2H, m), 2.14-2.22 (1H, m), 2.22-2.30 (1H, m),2.28-2.36 (1H, m), 4.42 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 5.55 (1H, br-s),6.38 (1H, d, J=15 Hz), 6.47 (1H, dd, J=3 Hz, 2 Hz), 6.58 (1H, d, J=3 Hz,1 Hz), 7.42 (1H, d, J=15 Hz), 7.46 (1H, dd, J=2 Hz, 1 Hz), 7.83 (1H, d,J=8 Hz), 9.59 (1H, d, 1 Hz)

REFERENCE EXAMPLE 200N-[[1-[(3-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol

0.52 ml (3.01 mmol) of diisopropylamine was added to a solution of 124mg (1.20 mmol) of L-valinol and 222 mg (1.00 mmol) of2-(3-furanyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one in 10 ml of toluene,and the mixture was stirred and heated under reflux for 4 days. Thereaction solution was distilled off under reduced pressure and theresidue was purified by silica gel chromatography to obtain 340 mg(quantitative) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz) 1.35-1.54(3H, m), 1.56-1.76 (3H, m), 1.82-1.90 (1H, m), 1.96-2.06 (2H, m),2.13-2.20 (2H, m), 3.05 (1H, br-s), 3.54-3.59 (1H, m), 3.69-3.78 (2H,m), 5.88 (1H, br-s), 6.60 (1H, dd, J=2 Hz, 1 Hz), 6.80 (1H, br-d, J=8Hz), 7.46 (1H, dd, J=2 Hz, 2 Hz), 7.96 (1H, dd, J=2 Hz, 1 Hz)

REFERENCE EXAMPLE 201N-[[1-[(3-Furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinal

340 mg of the above obtainedN-[[1-[(3-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valinol was usedinstead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin the process according to Reference Example 166 to obtain 282 mg(87.6%, 2 steps) of the title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.32-1.52(3H, m), 1.60-1.76 (3H, m), 1.95-2.06 (2H, m), 2.18-2.24 (1H, m),2.26-2.36 (2H, m), 4.46 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 5.74 (1H, br-s),6.62 (1H, dd, J=2 Hz, 1 Hz), 7.47 (1H, dd, J=2 Hz, 1 Hz), 7.71 (1H, d,J=8 Hz), 7.97 (1H, dd, J=1 Hz, 1 Hz), 9.61 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 202N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

260 mg (1.00 mmol) of2-(4-methoxyphenyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to asolution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate,and the mixture was stirred at room temperature for 4 days. The reactionsolution was distilled off under reduced pressure, and the residue waswashed with diethyl ether to obtain 243.5 mg (66.7%) of the titlecompound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz), 1.36-1.80(7H, m), 1.80-1.88 (1H, m), 1.98-2.10 (2H, m), 2.16-2.26 (2H, m), 3.55(1H, dd, J=11 Hz, 6 Hz), 3.69-3.74 (1H, m), 3.77 (1H, dd, J=11 Hz, 3Hz), 3.86 (3H, s), 6.17 (1H, br-s), 6.84 (1H′, br-d, J=9 Hz), 6.95 (2H,dd, J=7 Hz, 2 Hz), 7.74 (2H, dd, J=7 Hz, 2 Hz)

REFERENCE EXAMPLE 203N-[[1-[[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

243 mg (0.67 mmol) ofN-[[1-[[(4-methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin the process according to Reference Example 166 to obtain 240 mg(98.9%) of the title compound.

1H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.34-1.54(3H, m), 1.63-1.78 (3H, m), 1.96-2.05 (2H, m), 2.24-2.37 (3H, m), 3.87(3H, s), 4.43 (1H, ddd, J=8 Hz, 5 Hz, 1 Hz), 6.03 (1H, br-s), 6.96 (2H,dd, J=7 Hz, 2 Hz), 7.75 (2H, dd, J=7 Hz, 2 Hz), 7.87 (1H, d, J=8 Hz),9.60 (1H, s)

REFERENCE EXAMPLE 204N-[[1-[[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol

220 mg (1.01 mmol) of2-(1H-pyrrol-2-yl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to asolution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate,and the mixture was stirred at room temperature for 4 days. The reactionsolution was distilled off under reduced pressure, and the residue waspurified by silica gel chromatography to obtain 247 mg (76.4%) of thetitle compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz) 1.34-1.52(3H, m), 1.62-2.14 (8H, m), 2.16-2.22 (1H, m), 3.51 (1H, dd, J=12 Hz, 7Hz), 3.69-3.76 (2H, m), 6.03 (1H, br-s), 6.27 (1H, ddd, J=4 Hz, 3 Hz, 3Hz), 6.60-6.66 (2H, m), 6.97 (1H, ddd, J=3 Hz, 3 Hz, 1 Hz), 9.48 (1H,br-s)

REFERENCE EXAMPLE 205N-[[1-[[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinal

247 mg (0.77 mmol) ofN-[[1-[[(1H-pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-valinolwas used instead ofN-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycinolin the process according to Reference Example 166 to obtain 217 mg(88.2%) of the title compound.

1H-NMR (CDCl₃, δ): 0.93 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz) 1.32-1.52(3H, m), 1.60-1.76 (3H, m), 1.94-2.03 (2H, m), 2.18-2.25 (1H, m),2.26-2.34 (2H, m), 4.45 (1H, dd, J=8 Hz, 5 Hz), 5.84 (1H, br-s), 6.28(1H, ddd, J=4 Hz, 3 Hz, 3 Hz), 6.63 (1H, ddd, J=4 Hz, 3 Hz, 1 Hz), 6.96(1H, ddd, J=3 Hz, 3 Hz, 1 Hz), 7.75 (1H, br-d, J=8 Hz), 9.33 (1H, br-s),9.59 (1H, s)

TEST EXAMPLES Test Example 1 Measurement of Cathepsin K InhibitoryActivity

Active enzyme was produced by expressing cathepsin K in the form of aproenzyme in a cell culture from a baculovirus expression system usingSf21 insect cells, followed by incubating for 1 hour at 40° C.¹⁾.Cathepsin K activity was measured based on decomposition of thefluorescent substrate Z-Gly-Pro-Arg-MCA (Peptide Institute, Inc.) incompliance with the method of Aibe, et al.²⁾. Namely, the decompositionof 20 mM Z-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM sodiumpotassium phosphate, 1 mM EDTA and 8 mM cysteine at pH 6.0. The reactionwas carried out for 30 minutes at 37° C., and stopped by the addition of2×10⁻⁵ M Calpeptin. After stopping the reaction, fluorescent intensitywas measured at an excitation wavelength of 355 nm and measurementwavelength of 460 nm. Inhibition of cathepsin K by the compounds wasexamined using the reaction system described above. The 50% inhibitoryconcentrations on cathepsin K of the compounds of the reference examplesare shown in Table 1.

Test Example 2 Measurement of Cathepsin B Inhibitory Activity

Human cathepsin B (Calbiochem Corp.) was used for measurement. Activitywas measured based on decomposition of the fluorescent substrateZ-Arg-Arg-MCA (Peptide Institute, Inc.) in compliance with the method ofBarrett, et al.³⁾. Namely, the decomposition of 20 mM Z-Arg-Arg-MCA bycathepsin B was measured in 100 mM sodium potassium phosphate, 1 mMEDTA, 8 mM cysteine and 0.005% Brij35 at pH 6.0. The reaction wascarried out for 30 minutes at 30° C., and stopped by the addition of2×10⁻⁵ M Calpeptin. After stopping the reaction, fluorescent intensitywas measured at an excitation wavelength of 355 nm and measurementwavelength of 460 nm. Inhibition of cathepsin B by the compounds wasexamined using the reaction system described above. The 50% inhibitoryconcentrations on cathepsin B of the compounds of the reference examplesare shown in Table 1.

Test Example 3 Measurement of Cathepsin L Inhibitory Activity

Human cathepsin L (Calbiochem Corp.) was used for measurement. Activitywas measured based on decomposition of the fluorescent substrateZ-Phe-Arg-MCA (Peptide Institute, Inc.) in compliance with the method ofBarrett, et al.³⁾. Namely, the decomposition of 20 mM Z-Phe-Arg-MCA bycathepsin L was measured in 100 mM sodium acetate, 5 mM EDTA, 4 mM urea,8 mM cysteine and 0.005% Brij35 at pH 5.5. The reaction was carried outfor 30 minutes at 30° C., and stopped by the addition of 2×10⁻⁵ MCalpeptin. After stopping the reaction, fluorescent intensity wasmeasured at an excitation wavelength of 355 nm and measurementwavelength of 460 nm. Inhibition of cathepsin L by the compounds wasexamined using the reaction system described above. The 50% inhibitoryconcentrations on cathepsin L of the compounds of the reference examplesare shown in Table 1.

REFERENCES

-   Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)-   Aibe et al., Biol. Pharm. Bull., 19, 1026-1031 (1996)-   Barrett, A. J. & Kirschke, H. Methods Enzymol. 80, 535-561 (1981)

TABLE 1 IC₅₀ (M) Compound human human No. Structural Formula Cathepsin KCathepsin B Cathepsin L Reference Example 148

1.9 × 10⁻⁹  1.1 × 10⁻⁷ B/K 58 1.4 × 10⁻⁷ L/K 74 Reference Example 144

1.7 × 10⁻⁹  3.9 × 10⁻⁷ B/K 230 6.8 × 10⁻⁷ L/K 400 Reference Example 149

3.5 × 10⁻⁹  4.0 × 10⁻⁸ B/K 11 5.3 × 10⁻⁸ L/K 15 Reference Example 145

4.0 × 10⁻⁹  1.4 × 10⁻⁷ B/K 35 2.0 × 10⁻⁷ L/K 50 Reference Example 150

3.0 × 10⁻⁹  1.3 × 10⁻⁸ B/K 4.3 2.2 × 10⁻⁸ L/K 7.3 Reference Example 147

2.2 × 10⁻⁸  2.6 × 10⁻⁷ B/K 12 4.7 × 10⁻⁷ L/K 21 Reference Example 151

1.9 × 10⁻⁹  5.7 × 10⁻⁸ B/K 30 6.7 × 10⁻⁸ L/K 35 Reference Example 146

5.4 × 10⁻¹⁰ 4.7 × 10⁻⁸ B/K 87 2.0 × 10⁻⁷ L/K 370

1. An oxazolone derivative represented by formula (I):

[wherein, R¹ represents an unsubstituted alkyl group having 3 to 12carbon atoms, an alkyl group having 1 to 12 carbon atoms substitutedwith at least one substituent selected from the following group (a), analkenyl group having 2 to 12 carbon atoms optionally substituted with atleast one substituent selected from the following group (a), an alkynylgroup having 2 to 12 carbon atoms optionally substituted with at leastone substituent selected from the following group (a), a phenyl groupsubstituted with at least one substituent selected from the followinggroup (b), a naphthyl group optionally substituted with at least onesubstituent selected from the following group (a), or a heterocyclicgroup optionally substituted with at least one substituent selected fromthe following group (a); and, ring A represents a saturated cyclicalkylidene group having 6 to 7 carbon atoms; provided that, theheterocyclic group does not form a spiro ring, an alkyl group having 1to 12 carbon atoms substituted with at least one substituent selectedfrom the group (a) does not include a cyclohexyl group substituted withan amino group and a phenylmethoxycarbonylamino group, an isobutyl groupsubstituted with a phenylmethylamino group, a 3-pentyl group substitutedwith a heterocyclic group or a 1-carbonylaminocyclohexane carboxylgroup, or an n-butyl group substituted with3-oxa-1-azaspiro[4.5]dec-1-ene-4-one; an unsubstituted alkenyl groupdoes not include a vinyl group and a propenyl group, and a substitutedphenyl group does not simultaneously have a methyl group and a methoxygroup on the same benzene ring]; group (a): hydroxyl group, alkyl group,alkenyl group, alkynyl group, fluorine atom, chlorine atom, iodine atom,bromine atom, aromatic hydrocarbon group, heterocyclic group, alkoxygroup, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxygroup, arylthio group, acyl group, sulfonyl group, heterocyclyloxygroup, heterocyclylthio group, amido group, ureido group, carboxylgroup, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyanogroup, nitro group, acyloxy group, azido group, sulfonamido group,mercapto group, alkoxycarbonylamino group, and Rx(Ry)N group (wherein,Rx and Ry respectively and independently represent a hydrogen atom,alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon group orheterocyclic group); and group (b): hydroxyl group, alkyl group, alkenylgroup, alkynyl group, fluorine atom, chlorine atom, iodine atom,aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidinogroup, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthiogroup, acyl group, sulfonyl group, heterocyclyloxy group,heterocyclylthio group, amido group, ureido group, carboxyl group,carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group,nitro group, acyloxy group, azido group, sulfonamido group, mercaptogroup, alkoxycarbonylamino group, and Rx(Ry)N group (wherein, Rx and Ryrespectively and independently represent a hydrogen atom, alkyl group,alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclicgroup).
 2. An oxazolone derivative represented by formula (I′):

[wherein, R^(1′) represents an unsubstituted alkyl group having 3 to 12carbon atoms, an alkyl group having 1 to 12 carbon atoms substitutedwith at least one substituent selected from the following group (a₁), anunsubstituted alkenyl group having 4 to 12 carbon atoms, an alkenylgroup having 2 to 12 carbon atoms substituted with at least onesubstituent selected from the following group (a), an alkynyl grouphaving 2 to 12 carbon atoms optionally substituted with at least onesubstituent selected from the following group (a), a phenyl groupsubstituted with at least one substituent selected from the followinggroup (b₁), a naphthyl group optionally substituted with at least onesubstituent selected from the following group (a), or a heterocyclicgroup optionally substituted with at least one substituent selected fromthe following group (a); and, ring A represents a saturated cyclicalkylidene group having 6 to 7 carbon atoms, provided that theheterocyclic group does not form a spiro ring]; group (a₁): hydroxylgroup, alkyl group, alkenyl group, alkynyl group, fluorine atom,chlorine atom, iodine atom, bromine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, oxo group, sulfamoyl group, sulfogroup, cyano group, nitro group, acyloxy group, azido group, sulfonamidogroup, and mercapto group; group (a): hydroxyl group, alkyl group,alkenyl group, alkynyl group, fluorine atom, chlorine atom, iodine atom,bromine atom, aromatic hydrocarbon group, heterocyclic group, alkoxygroup, guanidino group, alkylthio group, alkoxycarbonyl group, aryloxygroup, arylthio group, acyl group, sulfonyl group, heterocyclyloxygroup, heterocyclylthio group, amido group, ureido group, carboxylgroup, carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyanogroup, nitro group, acyloxy group, azido group, sulfonamido group,mercapto group, alkoxycarbonylamino group, and Rx(Ry)N group (wherein,Rx and Ry respectively and independently represent a hydrogen atom,alkyl group, alkenyl group, alkynyl group, aromatic hydrocarbon group orheterocyclic group); and group (b₁): hydroxyl group, alkyl group having2 to 12 carbon atoms, alkenyl group, alkynyl group, fluorine atom,chlorine atom, iodine atom, aromatic hydrocarbon group, heterocyclicgroup, alkoxy group, guanidino group, alkylthio group, alkoxycarbonylgroup, aryloxy group, arylthio group, acyl group, sulfonyl group,heterocyclyloxy group, heterocyclylthio group, amido group, ureidogroup, carboxyl group, carbamoyl group, oxo group, sulfamoyl group,sulfo group, cyano group, nitro group, acyloxy group, azido group,sulfonamido group, mercapto group, alkoxycarbonylamino group, andRx(Ry)N group (wherein, Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group).
 3. An oxazolonederivative represented by formula (I″):

[wherein, R^(1″) represents an unsubstituted alkenyl group having 4 to12 carbon atoms, an alkenyl group having 2 to 12 carbon atomssubstituted with at least one substituent selected from the followinggroup (a), an alkynyl group having 2 to 12 carbon atoms optionallysubstituted with at least one substituent selected from the followinggroup (a), a phenyl group substituted with at least one substituentselected from the following group (b₁), a naphthyl group optionallysubstituted with a substituent selected from the following group (a), aheterocyclic group optionally substituted with at least one substituentselected from the following group (a), or a group represented byRa(Rb)CH—, and ring A represents a saturated cyclic alkylidene grouphaving 6 to 7 carbon atoms; wherein, in the case both Ra and Rb are nothydrogen atoms, Ra and Rb represent a hydroxyl group, fluorine atom,chlorine atom, iodine atom, bromine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, Rx(Ry)N group (wherein, Rx and Ry respectively and independentlyrepresent a hydrogen atom, alkyl group, alkenyl group, alkynyl group,aromatic hydrocarbon group or heterocyclic group), an alkyl group having1 to 12 carbon atoms substituted with at least one substituent selectedfrom the following group (a), unsubstituted alkyl group having 1 to 12carbon atoms, phenyl group optionally substituted with at least onesubstituent selected from the following group (a), naphthyl groupoptionally substituted with at least one substituent selected from thefollowing group (a), heterocyclic group optionally substituted with atleast one substituent selected from the following group (a), alkyl grouphaving 1 to 12 carbon atoms optionally substituted with at least onesubstituent selected from the following group (a), aromatic hydrocarbongroup optionally substituted with at least one substituent selected fromthe following group (a), or heterocyclic group optionally substitutedwith at least one substituent selected from the following group (a); andin the case either one of Ra and Rb is a hydrogen atom, the other Ra andRb represents a hydroxyl group, fluorine atom, chlorine atom, iodineatom, bromine atom, aromatic hydrocarbon group, heterocyclic group,alkoxy group, guanidino group, alkylthio group, alkoxycarbonyl group,aryloxy group, arylthio group, acyl group, sulfonyl group,heterocyclyloxy group, heterocyclylthio group, amido group, ureidogroup, carboxyl group, carbamoyl group, oxo group, sulfamoyl group,sulfo group, cyano group, nitro group, acyloxy group, azido group,sulfonamido group, mercapto group, alkoxycarbonylamino group, Rx(Ry)Ngroup (wherein, Rx and Ry respectively and independently represent ahydrogen atom, alkyl group, alkenyl group, alkynyl group, aromatichydrocarbon group or heterocyclic group), an alkyl group having 1 to 12carbon atoms substituted with at least one substituent selected from thefollowing group (a), unsubstituted alkyl group having 2 to 12 carbonatoms, phenyl group optionally substituted with at least one substituentselected from the following group (a), naphthyl group optionallysubstituted with at least one substituent selected from the followinggroup (a), or heterocyclic group optionally substituted with at leastone substituent selected from the following group (a), and aheterocyclic group does not form a spiro ring; group (a): hydroxylgroup, alkyl group, alkenyl group, alkynyl group, fluorine atom,chlorine atom, iodine atom, bromine atom, aromatic hydrocarbon group,heterocyclic group, alkoxy group, guanidino group, alkylthio group,alkoxycarbonyl group, aryloxy group, arylthio group, acyl group,sulfonyl group, heterocyclyloxy group, heterocyclylthio group, amidogroup, ureido group, carboxyl group, carbamoyl group, oxo group,sulfamoyl group, sulfo group, cyano group, nitro group, acyloxy group,azido group, sulfonamido group, mercapto group, alkoxycarbonylaminogroup, and Rx(Ry)N group (wherein, Rx and Ry respectively andindependently represent a hydrogen atom, alkyl group, alkenyl group,alkynyl group, aromatic hydrocarbon group or heterocyclic group); andgroup (b₁): hydroxyl group, alkyl group having 2 to 12 carbon atoms,alkenyl group, alkynyl group, fluorine atom, chlorine atom, iodine atom,aromatic hydrocarbon group, heterocyclic group, alkoxy group, guanidinogroup, alkylthio group, alkoxycarbonyl group, aryloxy group, arylthiogroup, acyl group, sulfonyl group, heterocyclyloxy group,heterocyclylthio group, amido group, ureido group, carboxyl group,carbamoyl group, oxo group, sulfamoyl group, sulfo group, cyano group,nitro group, acyloxy group, azido group, sulfonamido group, mercaptogroup, alkoxycarbonylamino group, and Rx(Ry)N group (wherein, Rx and Ryrespectively and independently represent a hydrogen atom, alkyl group,alkenyl group, alkynyl group, aromatic hydrocarbon group or heterocyclicgroup).
 4. The oxazolone derivative according to any one of claims 1 to3, wherein ring A in formula (I), (I′) or (I″) is a cyclohexylidenegroup.
 5. The oxazolone derivative according to any one of claims 1 to3, wherein R¹, R^(1′) or R^(1″) in formula (I), (I′) or (I″) is aheterocyclic group optionally substituted with at least one substituentselected from the group (a), a phenyl group substituted with at leastone substituent selected from the group (b₁), or an alkyl group having 1to 12 carbon atoms substituted with an aromatic hydrocarbon group orheterocyclic group.